Histone demethylase inhibitors

ABSTRACT

The present disclosure relates generally to compositions and methods for treating cancer and neoplastic disease. Provided herein are substituted pyridine derivative compounds and pharmaceutical compositions comprising said compounds. The subject compounds and compositions are useful for inhibition histone demethylase. Furthermore, the subject compounds and compositions are useful for the treatment of cancer, such as prostate cancer, breast cancer, bladder cancer, lung cancer and/or melanoma and the like.

CROSS-REFERENCE

This application claims the benefit of U.S. Provisional Application62/017,201, filed Jun. 25, 2014, which is incorporated herein byreference in its entirety.

BACKGROUND

A need exists in the art for an effective treatment of cancer andneoplastic disease.

BRIEF SUMMARY OF THE INVENTION

Provided herein are substituted pyridine derivative compounds andpharmaceutical compositions comprising said compounds. The subjectcompounds and compositions are useful for inhibition of histonedemethylase. Furthermore, the subject compounds and compositions areuseful for the treatment of cancer, such as prostate cancer, breastcancer, bladder cancer, lung cancer and/or melanoma and the like. Thesubstituted pyridine derivative compounds described herein are basedupon a disubstituted pyridine ring bearing at the 4-position acarboxylic acid, a carboxylic acid ester, or a carboxylic acidbioisostere thereof, and at the 3-position a substituted amino group.

One embodiment provides a compound, or a stereoisomer orpharmaceutically acceptable salt thereof, having the structure ofFormula (I):

wherein,

-   -   X is O or CH₂;    -   each R⁵, R⁶, R⁷ and R⁸ is independently chosen from hydrogen,        optionally substituted heterocyclyl, optionally substituted        heterocyclyloxy, optionally substituted heterocyclylalkyl,        optionally substituted heterocyclylalkoxy, optionally        substituted C₆-C₁₀ aryl-SO₂—, optionally substituted        heteroaryl-S—, or —N(R¹)(R²), wherein R¹ is hydrogen or        optionally substituted alkyl, and R² is chosen from optionally        substituted alkyl, optionally substituted aryl, optionally        substituted heteroaryl, optionally substituted heterocyclyl,        optionally substituted cycloalkyl, optionally substituted        cycloalkylalkyl, optionally substituted aryl-CO—, optionally        substituted heteroaryl-CO—, optionally substituted        cycloalkyl-CO—, or optionally substituted alkyl-CO—;        with the provision that at least one of R⁵, R⁶, R⁷ or R⁸ is not        hydrogen.

One embodiment provides a compound, or a stereoisomer orpharmaceutically acceptable salt thereof, having the structure ofFormula (II):

wherein,

-   -   X is O or CH₂;    -   R⁶ is chosen from optionally substituted heterocyclyl,        optionally substituted heterocyclyloxy, optionally substituted        heterocyclylalkyl, optionally substituted heterocyclylalkoxy,        optionally substituted C₆-C₁₀ aryl-SO₂—, optionally substituted        heteroaryl-S—, or —N(R¹)(R²), wherein R¹ is hydrogen or        optionally substituted alkyl, and R² is chosen from optionally        substituted alkyl, optionally substituted aryl, optionally        substituted heteroaryl, optionally substituted heterocyclyl,        optionally substituted cycloalkyl, optionally substituted        cycloalkylalkyl, optionally substituted aryl-CO—, optionally        substituted heteroaryl-CO—, optionally substituted        cycloalkyl-CO—, or optionally substituted alkyl-CO—; and    -   each R⁵, R⁷ and R⁸ is independently chosen from hydrogen,        halogen, —OH, —CN, optionally substituted C₁-C₆ alkyl,        optionally substituted C₁-C₆ alkoxy, optionally substituted        C₃-C₇ carbocyclyl, optionally substituted C₃-C₇ carbocyclyloxy,        optionally substituted C₄-C₁₂ carbocyclylalkyl, optionally        substituted C₄-C₁₂ carbocyclylalkoxy, optionally substituted        C₁-C₆ alkynyl, optionally substituted C₁-C₆ alkenyl, optionally        substituted C₆-C₁₀ aryl, optionally substituted C₆-C₁₀ aryloxy,        optionally substituted C₆-C₁₀ aryl-S—, optionally substituted        C₇-C₁₄ aralkoxy, optionally substituted heteroaryl, and        optionally substituted heteroaryloxy, optionally substituted        heterocyclyl, optionally substituted heterocyclyloxy,        substituted heterocyclylalkyl, optionally substituted        heterocyclylalkoxy, optionally substituted C₆-C₁₀ aryl-SO₂—,        optionally substituted heteroaryl-S—, or —N(R¹)(R²), wherein R¹        is hydrogen or optionally substituted alkyl, and R² is chosen        from optionally substituted alkyl, optionally substituted aryl,        optionally substituted heteroaryl, optionally substituted        heterocyclyl, optionally substituted cycloalkyl, optionally        substituted cycloalkylalkyl, optionally substituted aryl-CO—,        optionally substituted heteroaryl-CO—, optionally substituted        cycloalkyl-CO—, or optionally substituted alkyl-CO—;        with the provision that at least one of R⁵, R⁷ and R⁸ is        hydrogen.

One embodiment provides the compound of Formula (II), orpharmaceutically acceptable salt thereof, having the structure ofFormula (IIa):

wherein,

-   -   X is O or CH₂;    -   R⁶ is chosen from optionally substituted heterocyclyl,        optionally substituted heterocyclyloxy, optionally substituted        heterocyclylalkyl, optionally substituted heterocyclylalkoxy,        optionally substituted C₆-C₁₀ aryl-SO₂—, optionally substituted        heteroaryl-S—, or —N(R¹)(R²), wherein R¹ is hydrogen or        optionally substituted alkyl, and R² is chosen from optionally        substituted alkyl, optionally substituted aryl, optionally        substituted heteroaryl, optionally substituted heterocyclyl,        optionally substituted cycloalkyl, optionally substituted        cycloalkylalkyl, optionally substituted aryl-CO—, optionally        substituted heteroaryl-CO—, optionally substituted        cycloalkyl-CO—, or optionally substituted alkyl-CO—; and    -   each R⁵, R⁷ and R⁸ is independently chosen from hydrogen,        halogen, —OH, —CN, optionally substituted C₁-C₆ alkyl,        optionally substituted C₁-C₆ alkoxy, optionally substituted        C₃-C₇ carbocyclyl, optionally substituted C₃-C₇ carbocyclyloxy,        optionally substituted C₄-C₁₂ carbocyclylalkyl, optionally        substituted C₄-C₁₂ carbocyclylalkoxy, optionally substituted        C₁-C₆ alkynyl, optionally substituted C₁-C₆ alkenyl, optionally        substituted C₆-C₁₀ aryl, optionally substituted C₆-C₁₀ aryloxy,        optionally substituted C₆-C₁₀ aryl-S—, optionally substituted        C₇-C₁₄ aralkoxy, optionally substituted heteroaryl, and        optionally substituted heteroaryloxy, optionally substituted        heterocyclyl, optionally substituted heterocyclyloxy,        substituted heterocyclylalkyl, optionally substituted        heterocyclylalkoxy, optionally substituted C₆-C₁₀ aryl-SO₂—,        optionally substituted heteroaryl-S—, or —N(R¹)(R²), wherein R¹        is hydrogen or optionally substituted alkyl, and R² is chosen        from optionally substituted alkyl, optionally substituted aryl,        optionally substituted heteroaryl, optionally substituted        heterocyclyl, optionally substituted cycloalkyl, optionally        substituted cycloalkylalkyl, optionally substituted aryl-CO—,        optionally substituted heteroaryl-CO—, optionally substituted        cycloalkyl-CO—, or optionally substituted alkyl-CO—;

with the provision that at least one of R⁵, R⁷ and R⁸ is hydrogen.

One embodiment provides a compound, or a stereoisomer orpharmaceutically acceptable salt thereof, having the structure ofFormula (III):

wherein,

-   -   X is O or CH₂;    -   at least one of R⁵, R⁶, R⁷ and R⁸ is chosen from optionally        substituted heterocyclyl, optionally substituted        heterocyclyloxy, optionally substituted heterocyclylalkyl,        optionally substituted heterocyclylalkoxy, optionally        substituted C₆-C₁₀ aryl-SO₂—, optionally substituted        heteroaryl-S—, or —N(R¹)(R²), wherein R¹ is hydrogen or        optionally substituted alkyl, and R² is chosen from optionally        substituted alkyl, optionally substituted aryl, optionally        substituted heteroaryl, optionally substituted heterocyclyl,        optionally substituted cycloalkyl, optionally substituted        cycloalkylalkyl, optionally substituted aryl-CO—, optionally        substituted heteroaryl-CO—, optionally substituted        cycloalkyl-CO—, or optionally substituted alkyl-CO—; and    -   the remaining R⁵, R⁶, R⁷ and R⁸ groups are independently chosen        from hydrogen, halogen, —OH, —CN, optionally substituted C₁-C₆        alkyl, optionally substituted C₁-C₆ alkoxy, optionally        substituted C₃-C₇ carbocyclyl, optionally substituted C₃-C₇        carbocyclyloxy, optionally substituted C₄-C₁₂ carbocyclylalkyl,        optionally substituted C₄-C₁₂ carbocyclylalkoxy, optionally        substituted C₁-C₆ alkynyl, optionally substituted C₁-C₆ alkenyl,        optionally substituted C₆-C₁₀ aryl, optionally substituted        C₆-C₁₀ aryloxy, optionally substituted C₆-C₁₀ aryl-S—,        optionally substituted C₇-C₁₄ aralkoxy, optionally substituted        heteroaryl, and optionally substituted heteroaryloxy, optionally        substituted heterocyclyl, optionally substituted        heterocyclyloxy, substituted heterocyclylalkyl, optionally        substituted heterocyclylalkoxy, optionally substituted C₆-C₁₀        aryl-SO₂—, optionally substituted heteroaryl-S—, or —N(R¹)(R²),        wherein R¹ is hydrogen or optionally substituted alkyl, and R²        is chosen from optionally substituted alkyl, optionally        substituted aryl, optionally substituted heteroaryl, optionally        substituted heterocyclyl, optionally substituted cycloalkyl,        optionally substituted cycloalkylalkyl, optionally substituted        aryl-CO—, optionally substituted heteroaryl-CO—, optionally        substituted cycloalkyl-CO—, or optionally substituted alkyl-CO—.

One embodiment provides a compound, or a stereoisomer orpharmaceutically acceptable salt thereof, having the structure ofFormula (V):

wherein,

-   -   X is O or CH₂;    -   R⁶ is chosen from optionally substituted heterocyclyl,        optionally substituted heterocyclyloxy, optionally substituted        heterocyclylalkyl, optionally substituted heterocyclylalkoxy,        optionally substituted C₆-C₁₀ aryl-SO₂—, optionally substituted        heteroaryl-S—, or —N(R¹)(R²), wherein R¹ is hydrogen or        optionally substituted alkyl, and R² is chosen from optionally        substituted alkyl, optionally substituted aryl, optionally        substituted heteroaryl, optionally substituted heterocyclyl,        optionally substituted cycloalkyl, optionally substituted        cycloalkylalkyl, optionally substituted aryl-CO—, optionally        substituted heteroaryl-CO—, optionally substituted        cycloalkyl-CO—, or optionally substituted alkyl-CO—; and    -   each R⁵, R⁷ and R⁸ is independently chosen from hydrogen,        halogen, —OH, —CN, optionally substituted C₁-C₆ alkyl,        optionally substituted C₁-C₆ alkoxy, optionally substituted        C₃-C₇ carbocyclyl, optionally substituted C₃-C₇ carbocyclyloxy,        optionally substituted C₄-C₁₂ carbocyclylalkyl, optionally        substituted C₄-C₁₂ carbocyclylalkoxy, optionally substituted        C₁-C₆ alkynyl, optionally substituted C₁-C₆ alkenyl, optionally        substituted C₆-C₁₀ aryl, optionally substituted C₆-C₁₀ aryloxy,        optionally substituted C₆-C₁₀ aryl-S—, optionally substituted        C₇-C₁₄ aralkoxy, optionally substituted heteroaryl, and        optionally substituted heteroaryloxy, optionally substituted        heterocyclyl, optionally substituted heterocyclyloxy,        substituted heterocyclylalkyl, optionally substituted        heterocyclylalkoxy, optionally substituted C₆-C₁₀ aryl-SO₂—,        optionally substituted heteroaryl-S—, or —N(R¹)(R²), wherein R¹        is hydrogen or optionally substituted alkyl, and R² is chosen        from optionally substituted alkyl, optionally substituted aryl,        optionally substituted heteroaryl, optionally substituted        heterocyclyl, optionally substituted cycloalkyl, optionally        substituted cycloalkylalkyl, optionally substituted aryl-CO—,        optionally substituted heteroaryl-CO—, optionally substituted        cycloalkyl-CO—, or optionally substituted alkyl-CO—;

with the provision that at least one of R⁵, R⁷ and R⁸ is hydrogen.

One embodiment provides a pharmaceutical composition comprising apharmaceutically acceptable carrier and a substituted pyridinederivative compound as described herein, or a stereoisomer orpharmaceutically acceptable salt thereof.

One embodiment provides a method of inhibiting a histone demethylaseenzyme comprising contacting the histone demethylase enzyme with asubstituted pyridine derivative compound as described herein, or astereoisomer thereof.

One embodiment provides a method of treating cancer in a subject in needthereof, comprising administering to the subject a compositioncomprising a substituted pyridine derivative compound as describedherein, or a stereoisomer, or a pharmaceutically acceptable saltthereof.

INCORPORATION BY REFERENCE

All publications, patents, and patent applications mentioned in thisspecification are herein incorporated by reference to the same extent asif each individual publication, patent, or patent application wasspecifically and individually indicated to be incorporated by reference.

DETAILED DESCRIPTION OF THE INVENTION

As used herein and in the appended claims, the singular forms “a,”“and,” and “the” include plural referents unless the context clearlydictates otherwise. Thus, for example, reference to “an agent” includesa plurality of such agents, and reference to “the cell” includesreference to one or more cells (or to a plurality of cells) andequivalents thereof known to those skilled in the art, and so forth.When ranges are used herein for physical properties, such as molecularweight, or chemical properties, such as chemical formulae, allcombinations and subcombinations of ranges and specific embodimentstherein are intended to be included. The term “about” when referring toa number or a numerical range means that the number or numerical rangereferred to is an approximation within experimental variability (orwithin statistical experimental error), and thus the number or numericalrange may vary between 1% and 15% of the stated number or numericalrange. The term “comprising” (and related terms such as “comprise” or“comprises” or “having” or “including”) is not intended to exclude thatin other certain embodiments, for example, an embodiment of anycomposition of matter, composition, method, or process, or the like,described herein, may “consist of” or “consist essentially of” thedescribed features.

Definitions

As used in the specification and appended claims, unless specified tothe contrary, the following terms have the meaning indicated below.

“Amino” refers to the —NH₂ radical.

“Cyano” refers to the —CN radical.

“Nitro” refers to the —NO₂ radical.

“Oxa” refers to the —O— radical.

“Oxo” refers to the ═O radical.

“Thioxo” refers to the ═S radical.

“Imino” refers to the ═N—H radical.

“Oximo” refers to the ═N—OH radical.

“Hydrazino” refers to the ═N—NH₂ radical.

“Alkyl” refers to a straight or branched hydrocarbon chain radicalconsisting solely of carbon and hydrogen atoms, containing nounsaturation, having from one to fifteen carbon atoms (e.g., C₁-C₁₅alkyl). In certain embodiments, an alkyl comprises one to thirteencarbon atoms (e.g., C₁-C₁₃ alkyl). In certain embodiments, an alkylcomprises one to eight carbon atoms (e.g., C₁-C₈ alkyl). In otherembodiments, an alkyl comprises one to five carbon atoms (e.g., C₁-C₅alkyl). In other embodiments, an alkyl comprises one to four carbonatoms (e.g., C₁-C₄ alkyl). In other embodiments, an alkyl comprises oneto three carbon atoms (e.g., C₁-C₃ alkyl). In other embodiments, analkyl comprises one to two carbon atoms (e.g., C₁-C₂ alkyl). In otherembodiments, an alkyl comprises one carbon atom (e.g., C₁ alkyl). Inother embodiments, an alkyl comprises five to fifteen carbon atoms(e.g., C₅-C₁₅ alkyl). In other embodiments, an alkyl comprises five toeight carbon atoms (e.g., C₅-C₈ alkyl). In other embodiments, an alkylcomprises two to five carbon atoms (e.g., C₂-C₅ alkyl). In otherembodiments, an alkyl comprises two to ten carbon atoms (e.g., C₂-C₁₀alkyl). In other embodiments, an alkyl comprises three to five carbonatoms (e.g., C₃-C₅ alkyl). In other embodiments, the alkyl group isselected from methyl, ethyl, 1-propyl (n-propyl), 1-methylethyl(iso-propyl), 1-butyl (n-butyl), 1-methylpropyl (sec-butyl),2-methylpropyl (iso-butyl), 1,1-dimethylethyl (tert-butyl), 1-pentyl(n-pentyl). The alkyl is attached to the rest of the molecule by asingle bond. Unless stated otherwise specifically in the specification,an alkyl group is optionally substituted by one or more of the followingsubstituents: halo, cyano, nitro, oxo, thioxo, imino, oximo,trimethylsilanyl, —OR^(a), —SR^(a), —OC(O)—R^(a), —N(R^(a))₂,—C(O)R^(a), —C(O)OR^(a), —C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a),—OC(O)—N(R^(a))₂, —N(R^(a))C(O)R^(a), —N(R^(a))S(O)_(t)R^(a) (where t is1 or 2), —S(O)_(t)OR^(a) (where t is 1 or 2), —S(O)_(t)R^(a) (where t is1 or 2) and —S(O)_(t)N(R^(a))₂ (where t is 1 or 2) where each R^(a) isindependently hydrogen, alkyl, fluoroalkyl, carbocyclyl,carbocyclylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,heteroaryl or heteroarylalkyl.

“Alkenyl” refers to a straight or branched hydrocarbon chain radicalgroup consisting solely of carbon and hydrogen atoms, containing atleast one carbon-carbon double bond, and having from two to twelvecarbon atoms. In certain embodiments, an alkenyl comprises two to eightcarbon atoms. In other embodiments, an alkenyl comprises two to fourcarbon atoms. The alkenyl is attached to the rest of the molecule by asingle bond, for example, ethenyl (i.e., vinyl), prop-1-enyl (i.e.,allyl), but-1-enyl, pent-1-enyl, penta-1,4-dienyl, and the like. Unlessstated otherwise specifically in the specification, an alkenyl group isoptionally substituted by one or more of the following substituents:halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl,—OR^(a), —SR^(a), —OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a),—C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a), —OC(O)—N(R^(a))₂,—N(R^(a))C(O)R^(a), —N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2),—S(O)_(t)OR^(a) (where t is 1 or 2), —S(O)_(t)R^(a) (where t is 1 or 2)and —S(O)_(t)N(R^(a))₂ (where t is 1 or 2) where each R^(a) isindependently hydrogen, alkyl, fluoroalkyl, carbocyclyl,carbocyclylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,heteroaryl or heteroarylalkyl.

“Alkynyl” refers to a straight or branched hydrocarbon chain radicalgroup consisting solely of carbon and hydrogen atoms, containing atleast one carbon-carbon triple bond, having from two to twelve carbonatoms. In certain embodiments, an alkynyl comprises two to eight carbonatoms. In other embodiments, an alkynyl has two to four carbon atoms.The alkynyl is attached to the rest of the molecule by a single bond,for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and thelike. Unless stated otherwise specifically in the specification, analkynyl group is optionally substituted by one or more of the followingsubstituents: halo, cyano, nitro, oxo, thioxo, imino, oximo,trimethylsilanyl, —OR^(a), —SR^(a), —OC(O)—R^(a), —N(R^(a))₂,—C(O)R^(a), —C(O)OR^(a), —C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a),—OC(O)—N(R^(a))₂, —N(R^(a))C(O)R^(a), —N(R^(a))S(O)_(t)R^(a) (where t is1 or 2), —S(O)_(t)OR^(a) (where t is 1 or 2), —S(O)_(t)R^(a) (where t is1 or 2) and —S(O)_(t)N(R^(a))₂ (where t is 1 or 2) where each R^(a) isindependently hydrogen, alkyl, fluoroalkyl, carbocyclyl,carbocyclylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,heteroaryl or heteroarylalkyl.

“Alkylene” or “alkylene chain” refers to a straight or branched divalenthydrocarbon chain linking the rest of the molecule to a radical group,consisting solely of carbon and hydrogen, containing no unsaturation andhaving from one to twelve carbon atoms, for example, methylene,ethylene, propylene, n-butylene, and the like. The alkylene chain isattached to the rest of the molecule through a single bond and to theradical group through a single bond. The points of attachment of thealkylene chain to the rest of the molecule and to the radical group canbe through one carbon in the alkylene chain or through any two carbonswithin the chain. In certain embodiments, an alkylene comprises one toeight carbon atoms (e.g., C₁-C₈ alkylene). In other embodiments, analkylene comprises one to five carbon atoms (e.g., C₁-C₅ alkylene). Inother embodiments, an alkylene comprises one to four carbon atoms (e.g.,C₁-C₄ alkylene). In other embodiments, an alkylene comprises one tothree carbon atoms (e.g., C₁-C₃ alkylene). In other embodiments, analkylene comprises one to two carbon atoms (e.g., C₁-C₂ alkylene). Inother embodiments, an alkylene comprises one carbon atom (e.g., C₁alkylene). In other embodiments, an alkylene comprises five to eightcarbon atoms (e.g., C₅-C₈ alkylene). In other embodiments, an alkylenecomprises two to five carbon atoms (e.g., C₂-C₅ alkylene). In otherembodiments, an alkylene comprises three to five carbon atoms (e.g.,C₃-C₅ alkylene). Unless stated otherwise specifically in thespecification, an alkylene chain is optionally substituted by one ormore of the following substituents: halo, cyano, nitro, oxo, thioxo,imino, oximo, trimethylsilanyl, —OR^(a), SR^(a), —OC(O)—R^(a),—N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a), —C(O)N(R^(a))₂,—N(R^(a))C(O)OR^(a), —OC(O)—N(R^(a))₂, —N(R^(a))C(O)R^(a),—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —S(O)_(t)OR^(a) (where t is1 or 2), —S(O)_(t)R^(a) (where t is 1 or 2) and —S(O)_(t)N(R^(a))₂(where t is 1 or 2) where each R^(a) is independently hydrogen, alkyl,fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocyclyl,heterocyclylalkyl, heteroaryl or heteroarylalkyl.

“Aryl” refers to a radical derived from an aromatic monocyclic ormulticyclic hydrocarbon ring system by removing a hydrogen atom from aring carbon atom. The aromatic monocyclic or multicyclic hydrocarbonring system contains only hydrogen and carbon from five to eighteencarbon atoms, where at least one of the rings in the ring system isfully unsaturated, i.e., it contains a cyclic, delocalized (4n+2)π-electron system in accordance with the Hückel theory. The ring systemfrom which aryl groups are derived include, but are not limited to,groups such as benzene, fluorene, indane, indene, tetralin andnaphthalene. Unless stated otherwise specifically in the specification,the term “aryl” or the prefix “ar-” (such as in “aralkyl”) is meant toinclude aryl radicals optionally substituted by one or more substituentsindependently selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl,cyano, nitro, optionally substituted aryl, optionally substitutedaralkyl, optionally substituted aralkenyl, optionally substitutedaralkynyl, optionally substituted carbocyclyl, optionally substitutedcarbocyclylalkyl, optionally substituted heterocyclyl, optionallysubstituted heterocyclylalkyl, optionally substituted heteroaryl,optionally substituted heteroarylalkyl, —R^(b)—OR^(a),—R^(b)—OC(O)—R^(a), —R^(b)—OC(O)—OR^(a), —R^(b)—OC(O)—N(R^(a))₂,—R^(b)—N(R^(a))₂, —R^(b)—C (O)R^(a), —R^(b)—C(O)OR^(a),—R^(b)—C(O)N(R^(a))₂, —R^(b)—O—R^(c)—C(O)N(R^(a))₂,—R^(b)—N(R^(a))C(O)OR^(a), —R^(b)—N(R^(a))C(O)R^(a),—R^(b)—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —R^(b)—S(O)_(t)R^(a)(where t is 1 or 2), —R^(b)—S(O)_(t)OR^(a) (where t is 1 or 2) and—R^(b)—S(O)_(t)N(R^(a))₂ (where t is 1 or 2), where each R^(a) isindependently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl,aryl (optionally substituted with one or more halo groups), aralkyl,heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl, eachR^(b) is independently a direct bond or a straight or branched alkyleneor alkenylene chain, and R^(c) is a straight or branched alkylene oralkenylene chain, and where each of the above substituents isunsubstituted unless otherwise indicated.

“Aralkyl” refers to a radical of the formula —R^(c)-aryl where R^(c) isan alkylene chain as defined above, for example, methylene, ethylene,and the like. The alkylene chain part of the aralkyl radical isoptionally substituted as described above for an alkylene chain. Thearyl part of the aralkyl radical is optionally substituted as describedabove for an aryl group.

“Aralkenyl” refers to a radical of the formula —R^(d)-aryl where R^(d)is an alkenylene chain as defined above. The aryl part of the aralkenylradical is optionally substituted as described above for an aryl group.The alkenylene chain part of the aralkenyl radical is optionallysubstituted as defined above for an alkenylene group.

“Aralkynyl” refers to a radical of the formula —R^(e)-aryl, where R^(e)is an alkynylene chain as defined above. The aryl part of the aralkynylradical is optionally substituted as described above for an aryl group.The alkynylene chain part of the aralkynyl radical is optionallysubstituted as defined above for an alkynylene chain.

“Aralkoxy” refers to a radical bonded through an oxygen atom of theformula —O—R^(c)-aryl where R^(c) is an alkylene chain as defined above,for example, methylene, ethylene, and the like. The alkylene chain partof the aralkyl radical is optionally substituted as described above foran alkylene chain. The aryl part of the aralkyl radical is optionallysubstituted as described above for an aryl group.

“Carbocyclyl” refers to a stable non-aromatic monocyclic or polycyclichydrocarbon radical consisting solely of carbon and hydrogen atoms,which may include fused or bridged ring systems, having from three tofifteen carbon atoms. In certain embodiments, a carbocyclyl comprisesthree to ten carbon atoms. In other embodiments, a carbocyclyl comprisesfive to seven carbon atoms. The carbocyclyl is attached to the rest ofthe molecule by a single bond. Carbocyclyl may be saturated, (i.e.,containing single C—C bonds only) or unsaturated (i.e., containing oneor more double bonds or triple bonds.) A fully saturated carbocyclylradical is also referred to as “cycloalkyl.” Examples of monocycliccycloalkyls include, e.g., cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, and cyclooctyl. An unsaturated carbocyclyl isalso referred to as “cycloalkenyl.” Examples of monocyclic cycloalkenylsinclude, e.g., cyclopentenyl, cyclohexenyl, cycloheptenyl, andcyclooctenyl. Polycyclic carbocyclyl radicals include, for example,adamantyl, norbornyl (i.e., bicyclo[2.2.1]heptanyl), norbornenyl,decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Unlessotherwise stated specifically in the specification, the term“carbocyclyl” is meant to include carbocyclyl radicals that areoptionally substituted by one or more substituents independentlyselected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thioxo,cyano, nitro, optionally substituted aryl, optionally substitutedaralkyl, optionally substituted aralkenyl, optionally substitutedaralkynyl, optionally substituted carbocyclyl, optionally substitutedcarbocyclylalkyl, optionally substituted heterocyclyl, optionallysubstituted heterocyclylalkyl, optionally substituted heteroaryl,optionally substituted heteroarylalkyl, —R^(b)—OR^(a),—R^(b)—OC(O)—R^(a), —R^(b)—OC(O)—OR^(a), —R^(b)—OC(O)—N(R^(a))₂,—R^(b)—N(R^(a))₂, —R^(b)—C (O)R^(a), —R^(b)—C(O)OR^(a),—R^(b)—C(O)N(R^(a))₂, —R^(b)—O—R^(c)—C(O)N(R^(a))₂,—R^(b)—N(R^(a))C(O)OR^(a), —R^(b)—N(R^(a))C(O)R^(a),—R^(b)—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —R^(b)—S(O)_(t)R^(a)(where t is 1 or 2), —R^(b)—S(O)_(t)OR^(a) (where t is 1 or 2) and—R^(b)—S(O)_(t)N(R^(a))₂ (where t is 1 or 2), where each R^(a) isindependently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl,aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl orheteroarylalkyl, each R^(b) is independently a direct bond or a straightor branched alkylene or alkenylene chain, and R^(c) is a straight orbranched alkylene or alkenylene chain, and where each of the abovesubstituents is unsubstituted unless otherwise indicated.

“Carbocyclylalkyl” refers to a radical of the formula —R^(c)-carbocyclylwhere R^(c) is an alkylene chain as defined above. The alkylene chainand the carbocyclyl radical is optionally substituted as defined above.

“Carbocyclylalkoxy” refers to a radical bonded through an oxygen atom ofthe formula —O—R^(c)-carbocyclyl where R^(c) is an alkylene chain asdefined above. The alkylene chain and the carbocyclyl radical isoptionally substituted as defined above.

“Halo” or “halogen” refers to bromo, chloro, fluoro or iodosubstituents.

“Fluoroalkyl” refers to an alkyl radical, as defined above, that issubstituted by one or more fluoro radicals, as defined above, forexample, trifluoromethyl, difluoromethyl, fluoromethyl,2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like. Thealkyl part of the fluoroalkyl radical may be optionally substituted asdefined above for an alkyl group.

“Heterocyclyl” refers to a stable 3- to 18-membered non-aromatic ringradical that comprises two to twelve carbon atoms and from one to sixheteroatoms selected from nitrogen, oxygen and sulfur. Unless statedotherwise specifically in the specification, the heterocyclyl radical isa monocyclic, bicyclic, tricyclic or tetracyclic ring system, which mayinclude fused or bridged ring systems. The heteroatoms in theheterocyclyl radical may be optionally oxidized. One or more nitrogenatoms, if present, are optionally quaternized. The heterocyclyl radicalis partially or fully saturated. The heterocyclyl may be attached to therest of the molecule through any atom of the ring(s). Examples of suchheterocyclyl radicals include, but are not limited to, dioxolanyl,thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl,imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl,octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl,2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl,piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl,thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl,thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and1,1-dioxo-thiomorpholinyl. Unless stated otherwise specifically in thespecification, the term “heterocyclyl” is meant to include heterocyclylradicals as defined above that are optionally substituted by one or moresubstituents selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl,oxo, thioxo, cyano, nitro, optionally substituted aryl, optionallysubstituted aralkyl, optionally substituted aralkenyl, optionallysubstituted aralkynyl, optionally substituted carbocyclyl, optionallysubstituted carbocyclylalkyl, optionally substituted heterocyclyl,optionally substituted heterocyclylalkyl, optionally substitutedheteroaryl, optionally substituted heteroarylalkyl, —R^(b)—OR^(a),—R^(b)—OC(O)—R^(a), —R^(b)—OC(O)—OR^(a), —R^(b)—OC(O)—N(R^(a))₂,—R^(b)—N(R^(a))₂, —R^(b)—C (O)R^(a), —R^(b)—C(O)OR^(a),—R^(b)—C(O)N(R^(a))₂, —R^(b)—O—R^(c)—C(O)N(R^(a))₂,—R^(b)—N(R^(a))C(O)OR^(a), —R^(b)—N(R^(a))C(O)R^(a),—R^(b)—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —R^(b)—S(O)_(t)R^(a)(where t is 1 or 2), —R^(b)—S(O)_(t)OR^(a) (where t is 1 or 2) and—R^(b)—S(O)_(t)N(R^(a))₂ (where t is 1 or 2), where each R^(a) isindependently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl,aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl orheteroarylalkyl, each R^(b) is independently a direct bond or a straightor branched alkylene or alkenylene chain, and R^(c) is a straight orbranched alkylene or alkenylene chain, and where each of the abovesubstituents is unsubstituted unless otherwise indicated.

“N-heterocyclyl” or “N-attached heterocyclyl” refers to a heterocyclylradical as defined above containing at least one nitrogen and where thepoint of attachment of the heterocyclyl radical to the rest of themolecule is through a nitrogen atom in the heterocyclyl radical. AnN-heterocyclyl radical is optionally substituted as described above forheterocyclyl radicals. Examples of such N-heterocyclyl radicals include,but are not limited to, 1-morpholinyl, 1-piperidinyl, 1-piperazinyl,1-pyrrolidinyl, pyrazolidinyl, imidazolinyl, and imidazolidinyl.

“C-heterocyclyl” or “C-attached heterocyclyl” refers to a heterocyclylradical as defined above containing at least one heteroatom and wherethe point of attachment of the heterocyclyl radical to the rest of themolecule is through a carbon atom in the heterocyclyl radical. AC-heterocyclyl radical is optionally substituted as described above forheterocyclyl radicals. Examples of such C-heterocyclyl radicals include,but are not limited to, 2-morpholinyl, 2- or 3- or 4-piperidinyl,2-piperazinyl, 2- or 3-pyrrolidinyl, and the like.

“Heterocyclylalkyl” refers to a radical of the formula—R^(c)-heterocyclyl where R^(c) is an alkylene chain as defined above.If the heterocyclyl is a nitrogen-containing heterocyclyl, theheterocyclyl is optionally attached to the alkyl radical at the nitrogenatom. The alkylene chain of the heterocyclylalkyl radical is optionallysubstituted as defined above for an alkylene chain. The heterocyclylpart of the heterocyclylalkyl radical is optionally substituted asdefined above for a heterocyclyl group.

“Heterocyclylalkoxy” refers to a radical bonded through an oxygen atomof the formula —O—R^(c)-heterocyclyl where R^(c) is an alkylene chain asdefined above. If the heterocyclyl is a nitrogen-containingheterocyclyl, the heterocyclyl is optionally attached to the alkylradical at the nitrogen atom. The alkylene chain of theheterocyclylalkoxy radical is optionally substituted as defined abovefor an alkylene chain. The heterocyclyl part of the heterocyclylalkoxyradical is optionally substituted as defined above for a heterocyclylgroup.

“Heteroaryl” refers to a radical derived from a 3- to 18-memberedaromatic ring radical that comprises two to seventeen carbon atoms andfrom one to six heteroatoms selected from nitrogen, oxygen and sulfur.As used herein, the heteroaryl radical may be a monocyclic, bicyclic,tricyclic or tetracyclic ring system, wherein at least one of the ringsin the ring system is fully unsaturated, i.e., it contains a cyclic,delocalized (4n+2) π-electron system in accordance with the Hückeltheory. Heteroaryl includes fused or bridged ring systems. Theheteroatom(s) in the heteroaryl radical is optionally oxidized. One ormore nitrogen atoms, if present, are optionally quaternized. Theheteroaryl is attached to the rest of the molecule through any atom ofthe ring(s). Examples of heteroaryls include, but are not limited to,azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl,benzofuranyl, benzooxazolyl, benzo[d]thiazolyl, benzothiadiazolyl,benzo[b][1,4]dioxepinyl, benzo[b][1,4]oxazinyl, 1,4-benzodioxanyl,benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl,benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl(benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotriazolyl,benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl,cyclopenta[d]pyrimidinyl,6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl,5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl,6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazinyl, dibenzofuranyl,dibenzothiophenyl, furanyl, furanonyl, furo[3,2-c]pyridinyl,5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidinyl,5,6,7,8,9,10-hexahydrocycloocta[d]pyridazinyl,5,6,7,8,9,10-hexahydrocycloocta[d]pyridinyl, isothiazolyl, imidazolyl,indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl,isoquinolyl, indolizinyl, isoxazolyl,5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl,1,6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl,5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1-phenyl-1H-pyrrolyl,phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl,purinyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridinyl,pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrazinyl,pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl,quinolinyl, isoquinolinyl, tetrahydroquinolinyl,5,6,7,8-tetrahydroquinazolinyl,5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl,6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl,5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl,triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl,thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pyridinyl, and thiophenyl (i.e.thienyl). Unless stated otherwise specifically in the specification, theterm “heteroaryl” is meant to include heteroaryl radicals as definedabove which are optionally substituted by one or more substituentsselected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, haloalkenyl,haloalkynyl, oxo, thioxo, cyano, nitro, optionally substituted aryl,optionally substituted aralkyl, optionally substituted aralkenyl,optionally substituted aralkynyl, optionally substituted carbocyclyl,optionally substituted carbocyclylalkyl, optionally substitutedheterocyclyl, optionally substituted heterocyclylalkyl, optionallysubstituted heteroaryl, optionally substituted heteroarylalkyl,—R^(b)—OR^(a), —R^(b)—OC(O)—R^(a), —R^(b)—OC(O)—OR^(a),—R^(b)—OC(O)—N(R^(a))₂, —R^(b)—N(R^(a))₂, —R^(b)—C (O)R^(a),—R^(b)—C(O)OR^(a), —R^(b)—C(O)N(R^(a))₂, —R^(b)—O—R^(c)—C(O)N(R^(a))₂,—R^(b)—N(R^(a))C(O)OR^(a), —R^(b)—N(R^(a))C(O)R^(a),—R^(b)—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —R^(b)—S(O)_(t)R^(a)(where t is 1 or 2), —R^(b)—S(O)_(t)OR^(a) (where t is 1 or 2) and—R^(b)—S(O)_(t)N(R^(a))₂ (where t is 1 or 2), where each R^(a) isindependently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl,aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl orheteroarylalkyl, each R^(b) is independently a direct bond or a straightor branched alkylene or alkenylene chain, and R^(c) is a straight orbranched alkylene or alkenylene chain, and where each of the abovesubstituents is unsubstituted unless otherwise indicated.

“N-heteroaryl” refers to a heteroaryl radical as defined abovecontaining at least one nitrogen and where the point of attachment ofthe heteroaryl radical to the rest of the molecule is through a nitrogenatom in the heteroaryl radical. An N-heteroaryl radical is optionallysubstituted as described above for heteroaryl radicals.

“C-heteroaryl” refers to a heteroaryl radical as defined above and wherethe point of attachment of the heteroaryl radical to the rest of themolecule is through a carbon atom in the heteroaryl radical. AC-heteroaryl radical is optionally substituted as described above forheteroaryl radicals.

“Heteroarylalkyl” refers to a radical of the formula —R^(c)-heteroaryl,where R^(c) is an alkylene chain as defined above. If the heteroaryl isa nitrogen-containing heteroaryl, the heteroaryl is optionally attachedto the alkyl radical at the nitrogen atom. The alkylene chain of theheteroarylalkyl radical is optionally substituted as defined above foran alkylene chain. The heteroaryl part of the heteroarylalkyl radical isoptionally substituted as defined above for a heteroaryl group.

“Heteroarylalkoxy” refers to a radical bonded through an oxygen atom ofthe formula —O—R^(c)-heteroaryl, where R^(c) is an alkylene chain asdefined above. If the heteroaryl is a nitrogen-containing heteroaryl,the heteroaryl is optionally attached to the alkyl radical at thenitrogen atom. The alkylene chain of the heteroarylalkoxy radical isoptionally substituted as defined above for an alkylene chain. Theheteroaryl part of the heteroarylalkoxy radical is optionallysubstituted as defined above for a heteroaryl group.

As used herein, “carboxylic acid bioisostere” refers to a functionalgroup or moiety that exhibits similar physical, biological and/orchemical properties as a carboxylic acid moiety. Examples of carboxylicacid bioisosteres include, but are not limited to,

and the like.

The compounds, or their pharmaceutically acceptable salts, in someinstances, contain one or more asymmetric centers and thus give rise toenantiomers, diastereomers, and other stereoisomeric forms that aredefined, in terms of absolute stereochemistry, as (R)- or (S)- or, as(D)- or (L)- for amino acids. When the compounds described hereincontain olefinic double bonds or other centers of geometric asymmetry,and unless specified otherwise, it is intended that the compoundsinclude both E and Z geometric isomers (e.g., cis or trans). Likewise,all possible isomers, as well as their racemic and optically pure forms,and all tautomeric forms are also intended to be included. The term“geometric isomer” refers to E or Z geometric isomers (e.g., cis ortrans) of an alkene double bond. The term “positional isomer” refers tostructural isomers around a central ring, such as ortho-, meta-, andpara-isomers around a benzene ring.

A “stereoisomer” refers to a compound made up of the same atoms bondedby the same bonds but having different three-dimensional structures,which are not interchangeable. It is contemplated that the disclosureprovided herein encompasses the various stereoisomers and mixturesthereof and includes “enantiomers,” which refers to two stereoisomerswhose molecular structures are nonsuperimposable mirror images of oneanother.

A “tautomer” refers to a molecule wherein a proton shift from one atomof a molecule to another atom of the same molecule is possible. Thecompounds presented herein may, in certain embodiments, exist astautomers. In circumstances where tautomerization is possible, achemical equilibrium of the tautomers will exist. The exact ratio of thetautomers depends on several factors, including physical state,temperature, solvent, and pH. Some examples of tautomeric equilibriuminclude:

“Optional” or “optionally” means that a subsequently described event orcircumstance may or may not occur and that the description includesinstances when the event or circumstance occurs and instances in whichit does not. For example, “optionally substituted aryl” means that thearyl radical may or may not be substituted and that the descriptionincludes both substituted aryl radicals and aryl radicals having nosubstitution.

“Pharmaceutically acceptable salt” includes both acid and base additionsalts. A pharmaceutically acceptable salt of any one of the substitutedpyridine derivative compounds described herein is intended to encompassany and all pharmaceutically suitable salt forms. Preferredpharmaceutically acceptable salts of the compounds described herein arepharmaceutically acceptable acid addition salts and pharmaceuticallyacceptable base addition salts.

“Pharmaceutically acceptable acid addition salt” refers to those saltswhich retain the biological effectiveness and properties of the freebases, which are not biologically or otherwise undesirable, and whichare formed with inorganic acids such as hydrochloric acid, hydrobromicacid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid,hydrofluoric acid, phosphorous acid, and the like. Also included aresalts that are formed with organic acids such as aliphatic mono- anddicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoicacids, alkanedioic acids, aromatic acids, aliphatic and. aromaticsulfonic acids, etc. and include, for example, acetic acid,trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid,oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid,tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid,salicylic acid, and the like. Exemplary salts thus include sulfates,pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates,monohydrogenphosphates, dihydrogenphosphates, metaphosphates,pyrophosphates, chlorides, bromides, iodides, acetates,trifluoroacetates, propionates, caprylates, isobutyrates, oxalates,malonates, succinate suberates, sebacates, fumarates, maleates,mandelates, benzoates, chlorobenzoates, methylbenzoates,dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates,phenylacetates, citrates, lactates, malates, tartrates,methanesulfonates, and the like. Also contemplated are salts of aminoacids, such as arginates, gluconates, and galacturonates (see, forexample, Berge S. M. et al., “Pharmaceutical Salts,” Journal ofPharmaceutical Science, 66:1-19 (1997), which is hereby incorporated byreference in its entirety). Acid addition salts of basic compounds maybe prepared by contacting the free base forms with a sufficient amountof the desired acid to produce the salt according to methods andtechniques with which a skilled artisan is familiar.

“Pharmaceutically acceptable base addition salt” refers to those saltsthat retain the biological effectiveness and properties of the freeacids, which are not biologically or otherwise undesirable. These saltsare prepared from addition of an inorganic base or an organic base tothe free acid. Pharmaceutically acceptable base addition salts may beformed with metals or amines, such as alkali and alkaline earth metalsor organic amines. Salts derived from inorganic bases include, but arenot limited to, sodium, potassium, lithium, ammonium, calcium,magnesium, iron, zinc, copper, manganese, aluminum salts and the like.Salts derived from organic bases include, but are not limited to, saltsof primary, secondary, and tertiary amines, substituted amines includingnaturally occurring substituted amines, cyclic amines and basic ionexchange resins, for example, isopropylamine, trimethylamine,diethylamine, triethylamine, tripropylamine, ethanolamine,diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol,dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine,N,N-dibenzylethylenediamine, chloroprocaine, hydrabamine, choline,betaine, ethylenediamine, ethylenedianiline, N-methylglucamine,glucosamine, methylglucamine, theobromine, purines, piperazine,piperidine, N-ethylpiperidine, polyamine resins and the like. See Bergeet al., supra.

As used herein, “treatment” or “treating,” or “palliating” or“ameliorating” are used interchangeably herein. These terms refers to anapproach for obtaining beneficial or desired results including but notlimited to therapeutic benefit and/or a prophylactic benefit. By“therapeutic benefit” is meant eradication or amelioration of theunderlying disorder being treated. Also, a therapeutic benefit isachieved with the eradication or amelioration of one or more of thephysiological symptoms associated with the underlying disorder such thatan improvement is observed in the patient, notwithstanding that thepatient may still be afflicted with the underlying disorder. Forprophylactic benefit, the compositions may be administered to a patientat risk of developing a particular disease, or to a patient reportingone or more of the physiological symptoms of a disease, even though adiagnosis of this disease may not have been made.

“Prodrug” is meant to indicate a compound that may be converted underphysiological conditions or by solvolysis to a biologically activecompound described herein. Thus, the term “prodrug” refers to aprecursor of a biologically active compound that is pharmaceuticallyacceptable. A prodrug may be inactive when administered to a subject,but is converted in vivo to an active compound, for example, byhydrolysis. The prodrug compound often offers advantages of solubility,tissue compatibility or delayed release in a mammalian organism (see,e.g., Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier,Amsterdam).

A discussion of prodrugs is provided in Higuchi, T., et al., “Pro-drugsas Novel Delivery Systems,” A.C.S. Symposium Series, Vol. 14, and inBioreversible Carriers in Drug Design, ed. Edward B. Roche, AmericanPharmaceutical Association and Pergamon Press, 1987, both of which areincorporated in full by reference herein.

The term “prodrug” is also meant to include any covalently bondedcarriers, which release the active compound in vivo when such prodrug isadministered to a mammalian subject. Prodrugs of an active compound, asdescribed herein, may be prepared by modifying functional groups presentin the active compound in such a way that the modifications are cleaved,either in routine manipulation or in vivo, to the parent activecompound. Prodrugs include compounds wherein a hydroxy, amino ormercapto group is bonded to any group that, when the prodrug of theactive compound is administered to a mammalian subject, cleaves to forma free hydroxy, free amino or free mercapto group, respectively.Examples of prodrugs include, but are not limited to, acetate, formateand benzoate derivatives of alcohol or amine functional groups in theactive compounds and the like.

Substituted Pyridine Derivative Compounds

Substituted pyridine derivative compounds are described herein thatinhibit a histone demethylase enzyme. These compounds, and compositionscomprising these compounds, are useful for the treatment of cancer andneoplastic disease. The compounds described herein, in some embodiments,are useful for treating prostate cancer, breast cancer, bladder cancer,lung cancer and/or melanoma and the like.

One embodiment provides a compound, or a stereoisomer orpharmaceutically acceptable salt thereof, having the structure ofFormula (I):

wherein,

-   -   X is O or CH₂;    -   each R⁵, R⁶, R⁷ and R⁸ is independently chosen from hydrogen,        optionally substituted heterocyclyl, optionally substituted        heterocyclyloxy, optionally substituted heterocyclylalkyl,        optionally substituted heterocyclylalkoxy, optionally        substituted C₆-C₁₀ aryl-SO₂—, optionally substituted        heteroaryl-S—, or —N(R¹)(R²), wherein R¹ is hydrogen or        optionally substituted alkyl, and R² is chosen from optionally        substituted alkyl, optionally substituted aryl, optionally        substituted heteroaryl, optionally substituted heterocyclyl,        optionally substituted cycloalkyl, optionally substituted        cycloalkylalkyl, optionally substituted aryl-CO—, optionally        substituted heteroaryl-CO—, optionally substituted        cycloalkyl-CO—, or optionally substituted alkyl-CO—;

with the provision that at least one of R⁵, R⁶, R⁷ or R⁸ is nothydrogen.

Another embodiment provides the compound, or a stereoisomer orpharmaceutically acceptable salt thereof, of Formula (I), wherein X isO. Another embodiment provides the compound, or a stereoisomer orpharmaceutically acceptable salt thereof, of Formula (I), wherein X isCH₂.

Another embodiment provides the compound, or a stereoisomer orpharmaceutically acceptable salt thereof, of Formula (I), wherein R⁵ ishydrogen. Another embodiment provides the compound, or a stereoisomer orpharmaceutically acceptable salt thereof, of Formula (I), wherein R⁷ ishydrogen. Another embodiment provides the compound, or a stereoisomer orpharmaceutically acceptable salt thereof, of Formula (I), wherein R⁸ ishydrogen. Another embodiment provides the compound, or a stereoisomer orpharmaceutically acceptable salt thereof, of Formula (I), wherein R⁷ andR⁸ are hydrogen. Another embodiment provides the compound, or astereoisomer or pharmaceutically acceptable salt thereof, of Formula(I), wherein R⁶ is not hydrogen.

One embodiment provides a compound, or a stereoisomer orpharmaceutically acceptable salt thereof, having the structure ofFormula (II):

wherein,

-   -   X is O or CH₂;    -   R⁶ is chosen from optionally substituted heterocyclyl,        optionally substituted heterocyclyloxy, optionally substituted        heterocyclylalkyl, optionally substituted heterocyclylalkoxy,        optionally substituted C₆-C₁₀ aryl-SO₂—, optionally substituted        heteroaryl-S—, or —N(R¹)(R²), wherein R¹ is hydrogen or        optionally substituted alkyl, and R² is chosen from optionally        substituted alkyl, optionally substituted aryl, optionally        substituted heteroaryl, optionally substituted heterocyclyl,        optionally substituted cycloalkyl, optionally substituted        cycloalkylalkyl, optionally substituted aryl-CO—, optionally        substituted heteroaryl-CO—, optionally substituted        cycloalkyl-CO—, or optionally substituted alkyl-CO—; and    -   each R⁵, R⁷ and R⁸ is independently chosen from hydrogen,        halogen, —OH, —CN, optionally substituted C₁-C₆ alkyl,        optionally substituted C₁-C₆ alkoxy, optionally substituted        C₃-C₇ carbocyclyl, optionally substituted C₃-C₇ carbocyclyloxy,        optionally substituted C₄-C₁₂ carbocyclylalkyl, optionally        substituted C₄-C₁₂ carbocyclylalkoxy, optionally substituted        C₁-C₆ alkynyl, optionally substituted C₁-C₆ alkenyl, optionally        substituted C₆-C₁₀ aryl, optionally substituted C₆-C₁₀ aryloxy,        optionally substituted C₆-C₁₀ aryl-S—, optionally substituted        C₇-C₁₄ aralkoxy, optionally substituted heteroaryl, and        optionally substituted heteroaryloxy, optionally substituted        heterocyclyl, optionally substituted heterocyclyloxy,        substituted heterocyclylalkyl, optionally substituted        heterocyclylalkoxy, optionally substituted C₆-C₁₀ aryl-SO₂—,        optionally substituted heteroaryl-S—, or —N(R¹)(R²), wherein R¹        is hydrogen or optionally substituted alkyl, and R² is chosen        from optionally substituted alkyl, optionally substituted aryl,        optionally substituted heteroaryl, optionally substituted        heterocyclyl, optionally substituted cycloalkyl, optionally        substituted cycloalkylalkyl, optionally substituted aryl-CO—,        optionally substituted heteroaryl-CO—, optionally substituted        cycloalkyl-CO—, or optionally substituted alkyl-CO—;

with the provision that at least one of R⁵, R⁷ and R⁸ is hydrogen.

Another embodiment provides the compound, or a stereoisomer orpharmaceutically acceptable salt thereof, of Formula (II), wherein X isO. Another embodiment provides the compound, or a stereoisomer orpharmaceutically acceptable salt thereof, of Formula (II), wherein X isCH₂. Another embodiment provides the compound, or a stereoisomer orpharmaceutically acceptable salt thereof, of Formula (II), wherein eachR⁵, R⁷ and R⁸ is independently chosen from hydrogen, halogen, —OH, —CN,optionally substituted C₁-C₆ alkyl, or optionally substituted C₁-C₆alkoxy.

Another embodiment provides the compound, or a stereoisomer orpharmaceutically acceptable salt thereof, of Formula (II), wherein R⁵ ishydrogen. Another embodiment provides the compound, or a stereoisomer orpharmaceutically acceptable salt thereof, of Formula (II), wherein R⁷ ishydrogen. Another embodiment provides the compound, or a stereoisomer orpharmaceutically acceptable salt thereof, of Formula (II), wherein R⁸ ishydrogen. Another embodiment provides the compound, or a stereoisomer orpharmaceutically acceptable salt thereof, of Formula (II), wherein R⁷and R⁸ are hydrogen. Another embodiment provides the compound, or astereoisomer or pharmaceutically acceptable salt thereof, of Formula(II), wherein R⁶ is not hydrogen.

Another embodiment provides the compound, or a stereoisomer orpharmaceutically acceptable salt thereof, of Formula (II), wherein R⁶ isoptionally substituted heterocyclyl. Another embodiment provides thecompound, or a stereoisomer or pharmaceutically acceptable salt thereof,of Formula (II), wherein R⁶ is optionally substituted heterocyclyloxy.Another embodiment provides the compound, or a stereoisomer orpharmaceutically acceptable salt thereof, of Formula (II), wherein R⁶ isoptionally substituted heterocyclylalkyl. Another embodiment providesthe compound, or a stereoisomer or pharmaceutically acceptable saltthereof, of Formula (II), wherein R⁶ is optionally substitutedheterocyclylalkoxy. Another embodiment provides the compound, or astereoisomer or pharmaceutically acceptable salt thereof, of Formula(II), wherein R⁶ is optionally substituted C₆-C₁₀ aryl-SO₂—, oroptionally substituted heteroaryl-S—.

Another embodiment provides the compound, or a stereoisomer orpharmaceutically acceptable salt thereof, of Formula (II), wherein R⁶ is—N(R¹)(R²), wherein R¹ is hydrogen and R² is chosen from optionallysubstituted alkyl, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted heterocyclyl, optionally substitutedcycloalkyl, optionally substituted cycloalkylalkyl, optionallysubstituted aryl-CO—, optionally substituted heteroaryl-CO—, optionallysubstituted cycloalkyl-CO—, or optionally substituted alkyl-CO—. Anotherembodiment provides the compound, or a stereoisomer or pharmaceuticallyacceptable salt thereof, of Formula (II), wherein R⁶ is —N(R¹)(R²),wherein R¹ is optionally substituted alkyl and R² is chosen fromoptionally substituted alkyl, optionally substituted aryl, optionallysubstituted heteroaryl, optionally substituted heterocyclyl, optionallysubstituted cycloalkyl, optionally substituted cycloalkylalkyl,optionally substituted aryl-CO—, optionally substituted heteroaryl-CO—,optionally substituted cycloalkyl-CO—, or optionally substitutedalkyl-CO—. Another embodiment provides the compound, or a stereoisomeror pharmaceutically acceptable salt thereof, of Formula (II), wherein R⁶is —N(R¹)(R²), and R² is optionally substituted alkyl. Anotherembodiment provides the compound, or a stereoisomer or pharmaceuticallyacceptable salt thereof, of Formula (II), wherein R⁶ is —N(R¹)(R²), andR² is optionally substituted aryl. Another embodiment provides thecompound, or a stereoisomer or pharmaceutically acceptable salt thereof,of Formula (II), wherein R⁶ is —N(R¹)(R²), and R² is optionallysubstituted heteroaryl. Another embodiment provides the compound, or astereoisomer or pharmaceutically acceptable salt thereof, of Formula(II), wherein R⁶ is —N(R¹)(R²), and R² is optionally substitutedheterocyclyl. Another embodiment provides the compound, or astereoisomer or pharmaceutically acceptable salt thereof, of Formula(II), wherein R⁶ is —N(R¹)(R²), and R² is optionally substitutedcycloalkyl. Another embodiment provides the compound, or a stereoisomeror pharmaceutically acceptable salt thereof, of Formula (II), wherein R⁶is —N(R¹)(R²), and R² is optionally substituted cycloalkylalkyl. Anotherembodiment provides the compound, or a stereoisomer or pharmaceuticallyacceptable salt thereof, of Formula (II), wherein R⁶ is —N(R¹)(R²), andR² is optionally substituted aryl-CO—. Another embodiment provides thecompound, or a stereoisomer or pharmaceutically acceptable salt thereof,of Formula (II), wherein R⁶ is —N(R¹)(R²), and R² is optionallysubstituted heteroaryl-CO—. Another embodiment provides the compound, ora stereoisomer or pharmaceutically acceptable salt thereof, of Formula(II), wherein R⁶ is —N(R¹)(R²), and R² is optionally substitutedcycloalkyl-CO—. Another embodiment provides the compound, or astereoisomer or pharmaceutically acceptable salt thereof, of Formula(II), wherein R⁶ is —N(R¹)(R²), and R² is optionally substitutedalkyl-CO—.

One embodiment provides the compound of Formula (II), orpharmaceutically acceptable salt thereof, having the structure ofFormula (IIa):

wherein,

-   -   X is O or CH₂;    -   R⁶ is chosen from optionally substituted heterocyclyl,        optionally substituted heterocyclyloxy, optionally substituted        heterocyclylalkyl, optionally substituted heterocyclylalkoxy,        optionally substituted C₆-C₁₀ aryl-SO₂—, optionally substituted        heteroaryl-S—, or —N(R¹)(R²), wherein R¹ is hydrogen or        optionally substituted alkyl, and R² is chosen from optionally        substituted alkyl, optionally substituted aryl, optionally        substituted heteroaryl, optionally substituted heterocyclyl,        optionally substituted cycloalkyl, optionally substituted        cycloalkylalkyl, optionally substituted aryl-CO—, optionally        substituted heteroaryl-CO—, optionally substituted        cycloalkyl-CO—, or optionally substituted alkyl-CO—; and    -   each R⁵, R⁷ and R⁸ is independently chosen from hydrogen,        halogen, —OH, —CN, optionally substituted C₁-C₆ alkyl,        optionally substituted C₁-C₆ alkoxy, optionally substituted        C₃-C₇ carbocyclyl, optionally substituted C₃-C₇ carbocyclyloxy,        optionally substituted C₄-C₁₂ carbocyclylalkyl, optionally        substituted C₄-C₁₂ carbocyclylalkoxy, optionally substituted        C₁-C₆ alkynyl, optionally substituted C₁-C₆ alkenyl, optionally        substituted C₆-C₁₀ aryl, optionally substituted C₆-C₁₀ aryloxy,        optionally substituted C₆-C₁₀ aryl-S—, optionally substituted        C₇-C₁₄ aralkoxy, optionally substituted heteroaryl, and        optionally substituted heteroaryloxy, optionally substituted        heterocyclyl, optionally substituted heterocyclyloxy,        substituted heterocyclylalkyl, optionally substituted        heterocyclylalkoxy, optionally substituted C₆-C₁₀ aryl-SO₂—,        optionally substituted heteroaryl-S—, or —N(R¹)(R²), wherein R¹        is hydrogen or optionally substituted alkyl, and R² is chosen        from optionally substituted alkyl, optionally substituted aryl,        optionally substituted heteroaryl, optionally substituted        heterocyclyl, optionally substituted cycloalkyl, optionally        substituted cycloalkylalkyl, optionally substituted aryl-CO—,        optionally substituted heteroaryl-CO—, optionally substituted        cycloalkyl-CO—, or optionally substituted alkyl-CO—;

with the provision that at least one of R⁵, R⁷ and R⁸ is hydrogen.

Another embodiment provides the compound of Formula (IIa), orpharmaceutically acceptable salt thereof, wherein X is O. Anotherembodiment provides the compound of Formula (IIa), or pharmaceuticallyacceptable salt thereof, wherein X is CH₂.

Another embodiment provides the compound of Formula (IIa), orpharmaceutically acceptable salt thereof, wherein R⁵ is hydrogen.Another embodiment provides the compound of Formula (IIa), orpharmaceutically acceptable salt thereof, wherein R⁷ is hydrogen.Another embodiment provides the compound of Formula (IIa), orpharmaceutically acceptable salt thereof, wherein R⁸ is hydrogen.Another embodiment provides the compound of Formula (IIa), orpharmaceutically acceptable salt thereof, wherein R⁵, R⁷ and R⁸ arehydrogen. Another embodiment provides the compound of Formula (IIa), orpharmaceutically acceptable salt thereof, wherein X is O; and R⁵, R⁷ andR⁸ are hydrogen.

Another embodiment provides the compound of Formula (IIa), orpharmaceutically acceptable salt thereof, wherein R⁶ is optionallysubstituted heterocyclyl, or optionally substituted heterocyclyloxy.

Another embodiment provides the compound of Formula (IIa), orpharmaceutically acceptable salt thereof, wherein R⁶ is optionallysubstituted C₆-C₁₀ aryl-SO₂—, or optionally substituted heteroaryl-S—.

Another embodiment provides the compound of Formula (IIa), orpharmaceutically acceptable salt thereof, wherein R⁶ is —N(R¹)(R²),wherein R¹ is hydrogen; and R² is chosen from optionally substitutedalkyl, optionally substituted aryl, optionally substituted heteroaryl,optionally substituted heterocyclyl, optionally substituted cycloalkyl,optionally substituted cycloalkylalkyl, optionally substituted aryl-CO—,optionally substituted heteroaryl-CO—, optionally substitutedcycloalkyl-CO—, or optionally substituted alkyl-CO—.

Another embodiment provides the compound of Formula (IIa), orpharmaceutically acceptable salt thereof, wherein R⁶ is —N(R¹)(R²),wherein R¹ is optionally substituted alkyl; and R² is chosen fromoptionally substituted alkyl, optionally substituted aryl, optionallysubstituted heteroaryl, optionally substituted heterocyclyl, optionallysubstituted cycloalkyl, optionally substituted cycloalkylalkyl,optionally substituted aryl-CO—, optionally substituted heteroaryl-CO—,optionally substituted cycloalkyl-CO—, or optionally substitutedalkyl-CO—.

Another embodiment provides the compound of Formula (IIa), orpharmaceutically acceptable salt thereof, wherein R⁵, R⁷ and R⁸ arehydrogen; R⁶ is —N(R¹)(R²), wherein R¹ is optionally substituted alkyl;and R² is chosen from optionally substituted alkyl, optionallysubstituted aryl, optionally substituted heteroaryl, optionallysubstituted heterocyclyl, optionally substituted cycloalkyl, optionallysubstituted cycloalkylalkyl, optionally substituted aryl-CO—, optionallysubstituted heteroaryl-CO—, optionally substituted cycloalkyl-CO—, oroptionally substituted alkyl-CO—.

Another embodiment provides the compound of Formula (IIa), orpharmaceutically acceptable salt thereof, wherein R⁵, R⁷ and R⁸ arehydrogen; R⁶ is —N(R¹)(R²), wherein R¹ is optionally substituted alkyl;and R² is optionally substituted aryl.

Another embodiment provides the compound of Formula (IIa), orpharmaceutically acceptable salt thereof, wherein R⁵, R⁷ and R⁸ arehydrogen; R⁶ is —N(R¹)(R²), wherein R¹ is optionally substituted alkyl;and R² is optionally substituted heteroaryl.

Another embodiment provides the compound of Formula (IIa), orpharmaceutically acceptable salt thereof, wherein R⁵, R⁷ and R⁸ arehydrogen; R⁶ is —N(R¹)(R²), wherein R¹ is optionally substituted alkyl;and R² is optionally substituted heterocyclyl, optionally substitutedcycloalkyl, optionally substituted cycloalkylalkyl, optionallysubstituted aryl-CO—, optionally substituted cycloalkyl-CO—, oroptionally substituted alkyl-CO—.

Another embodiment provides the compound of Formula (IIa), orpharmaceutically acceptable salt thereof, wherein R⁵, R⁷ and R⁸ arehydrogen; R⁶ is —N(R¹)(R²), wherein R¹ is an optionally substitutedC1-C3 alkyl; and R² is optionally substituted aryl. Another embodimentprovides the compound of Formula (IIa), or pharmaceutically acceptablesalt thereof, wherein X is O; R⁵, R⁷ and R⁸ are hydrogen; R⁶ is—N(R¹)(R²), wherein R¹ is an optionally substituted C1-C3 alkyl; and R²is optionally substituted aryl.

Another embodiment provides the compound of Formula (IIa), orpharmaceutically acceptable salt thereof, wherein R⁵, R⁷ and R⁸ arehydrogen; R⁶ is —N(R¹)(R²), wherein R¹ is a CH₃ group; and R² isoptionally substituted aryl. Another embodiment provides the compound ofFormula (IIa), or pharmaceutically acceptable salt thereof, wherein X isO; R⁵, R⁷ and R⁸ are hydrogen; R⁶ is —N(R¹)(R²), wherein R¹ is a CH₃group; and R² is optionally substituted aryl.

Another embodiment provides the compound of Formula (IIa), orpharmaceutically acceptable salt thereof, wherein R⁵, R⁷ and R⁸ arehydrogen; R⁶ is —N(R¹)(R²), wherein R¹ is optionally substituted alkyl;and R² is optionally substituted aryl substituted with at least onesubstituent selected from optionally substituted C1-C5 alkyl, optionallysubstituted C2-C5 alkenyl, halogen, cyano, hydroxy, amino, optionallysubstituted C1-C5 alkoxy, optionally substituted alkylamino, optionallysubstituted dialkylamino, optionally substituted heterocyclyl,optionally substituted heteroaryl, optionally substituted cycloalkyl,optionally substituted cycloalkylalkyl, optionally substitutedcycloalkylalkoxy, or optionally substituted cycloalkoxy. Anotherembodiment provides the compound of Formula (IIa), or pharmaceuticallyacceptable salt thereof, wherein X is O; R⁵, R⁷ and R⁸ are hydrogen; R⁶is —N(R¹)(R²), wherein R¹ is optionally substituted alkyl; and R² isoptionally substituted aryl substituted with at least one substituentselected from optionally substituted C1-C5 alkyl, optionally substitutedC2-C5 alkenyl, halogen, cyano, hydroxy, amino, optionally substitutedC1-C5 alkoxy, optionally substituted alkylamino, optionally substituteddialkylamino, optionally substituted heterocyclyl, optionallysubstituted heteroaryl, optionally substituted cycloalkyl, optionallysubstituted cycloalkylalkyl, optionally substituted cycloalkylalkoxy, oroptionally substituted cycloalkoxy.

Another embodiment provides the compound of Formula (IIa), orpharmaceutically acceptable salt thereof, wherein R⁵, R⁷ and R⁸ arehydrogen; R⁶ is —N(R¹)(R²), wherein R¹ is optionally substituted alkyl;and R² is optionally substituted aryl substituted with at least onesubstituent selected from optionally substituted C1-C5 alkyl, halogen,optionally substituted C1-C5 alkoxy, optionally substitutedheterocyclyl, optionally substituted heteroaryl, optionally substitutedcycloalkyl, optionally substituted cycloalkylalkyl, optionallysubstituted cycloalkylalkoxy, or optionally substituted cycloalkoxy.Another embodiment provides the compound of Formula (IIa), orpharmaceutically acceptable salt thereof, wherein X is O; R⁵, R⁷ and R⁸are hydrogen; R⁶ is —N(R¹)(R²), wherein R¹ is optionally substitutedalkyl; and R² is optionally substituted aryl substituted with at leastone substituent selected from optionally substituted C1-C5 alkyl,halogen, optionally substituted C1-C5 alkoxy, optionally substitutedheterocyclyl, optionally substituted heteroaryl, optionally substitutedcycloalkyl, optionally substituted cycloalkylalkyl, optionallysubstituted cycloalkylalkoxy, or optionally substituted cycloalkoxy.

Another embodiment provides the compound of Formula (IIa), orpharmaceutically acceptable salt thereof, wherein R⁵, R⁷ and R⁸ arehydrogen; R⁶ is —N(R¹)(R²), wherein R¹ is optionally substituted alkyl;and R² is optionally substituted aryl substituted with at least onesubstituent selected from optionally substituted heterocyclyl,optionally substituted heteroaryl, optionally substituted cycloalkyl,optionally substituted cycloalkylalkyl, optionally substitutedcycloalkylalkoxy, or optionally substituted cycloalkoxy. Anotherembodiment provides the compound of Formula (IIa), or pharmaceuticallyacceptable salt thereof, wherein X is O; R⁵, R⁷ and R⁸ are hydrogen; R⁶is —N(R¹)(R²), wherein R¹ is optionally substituted alkyl; and R² isoptionally substituted aryl substituted with at least one substituentselected from optionally substituted heterocyclyl, optionallysubstituted heteroaryl, optionally substituted cycloalkyl, optionallysubstituted cycloalkylalkyl, optionally substituted cycloalkylalkoxy, oroptionally substituted cycloalkoxy.

Another embodiment provides the compound of Formula (IIa), orpharmaceutically acceptable salt thereof, wherein R⁵, R⁷ and R⁸ arehydrogen; R⁶ is —N(R¹)(R²), wherein R¹ is optionally substituted alkyl;and R² is optionally substituted aryl substituted with at least onesubstituent selected from optionally substituted C1-C5 alkyl, halogen,or optionally substituted C1-C5 alkoxy. Another embodiment provides thecompound of Formula (IIa), or pharmaceutically acceptable salt thereof,wherein X is O; R⁵, R⁷ and R⁸ are hydrogen; R⁶ is —N(R¹)(R²), wherein R¹is optionally substituted alkyl; and R² is optionally substituted arylsubstituted with at least one substituent selected from optionallysubstituted C1-C5 alkyl, halogen, or optionally substituted C1-C5alkoxy.

Another embodiment provides the compound of Formula (IIa), orpharmaceutically acceptable salt thereof, wherein R⁵, R⁷ and R⁸ arehydrogen; R⁶ is —N(R¹)(R²), wherein R¹ is optionally substituted alkyl;and R² is optionally substituted aryl substituted with at least oneoptionally substituted C1-C5 alkyl. Another embodiment provides thecompound of Formula (IIa), or pharmaceutically acceptable salt thereof,wherein X is O; R⁵, R⁷ and R⁸ are hydrogen; R⁶ is —N(R¹)(R²), wherein R¹is optionally substituted alkyl; and R² is optionally substituted arylsubstituted with at least one optionally substituted C1-C5 alkyl.

Another embodiment provides the compound of Formula (IIa), orpharmaceutically acceptable salt thereof, wherein X is O; R⁵, R⁷ and R⁸are hydrogen; R⁶ is —N(R¹)(R²), wherein R¹ is a CH₃ group; and R² isoptionally substituted aryl substituted with at least one substituentselected from optionally substituted C1-C5 alkyl, halogen, or optionallysubstituted C1-C5 alkoxy.

Another embodiment provides the compound of Formula (IIa), orpharmaceutically acceptable salt thereof, having the structure:

Another embodiment provides the compound of Formula (IIa), orpharmaceutically acceptable salt thereof, having the structure:

Another embodiment provides the compound of Formula (IIa), orpharmaceutically acceptable salt thereof, having the structure:

Another embodiment provides the compound of Formula (IIa), orpharmaceutically acceptable salt thereof, selected from:

Another embodiment provides the compound of Formula (IIa), orpharmaceutically acceptable salt thereof, selected from:

Another embodiment provides the compound of Formula (IIa), orpharmaceutically acceptable salt thereof, selected from:

Another embodiment provides the compound of Formula (IIa), orpharmaceutically acceptable salt thereof, selected from:

One embodiment provides a compound, or a stereoisomer orpharmaceutically acceptable salt thereof, having the structure ofFormula (III):

wherein,

-   -   X is O or CH₂;    -   at least one of R⁵, R⁶, R⁷ and R⁸ is chosen from optionally        substituted heterocyclyl, optionally substituted        heterocyclyloxy, optionally substituted heterocyclylalkyl,        optionally substituted heterocyclylalkoxy, optionally        substituted C₆-C₁₀ aryl-SO₂—, optionally substituted        heteroaryl-S—, or —N(R¹)(R²), wherein R¹ is hydrogen or        optionally substituted alkyl, and R² is chosen from optionally        substituted alkyl, optionally substituted aryl, optionally        substituted heteroaryl, optionally substituted heterocyclyl,        optionally substituted cycloalkyl, optionally substituted        cycloalkylalkyl, optionally substituted aryl-CO—, optionally        substituted heteroaryl-CO—, optionally substituted        cycloalkyl-CO—, or optionally substituted alkyl-CO—; and    -   the remaining R⁵, R⁶, R⁷ and R⁸ groups are independently chosen        from hydrogen, halogen, —OH, —CN, optionally substituted C₁-C₆        alkyl, optionally substituted C₁-C₆ alkoxy, optionally        substituted C₃-C₇ carbocyclyl, optionally substituted C₃-C₇        carbocyclyloxy, optionally substituted C₄-C₁₂ carbocyclylalkyl,        optionally substituted C₄-C₁₂ carbocyclylalkoxy, optionally        substituted C₁-C₆ alkynyl, optionally substituted C₁-C₆ alkenyl,        optionally substituted C₆-C₁₀ aryl, optionally substituted        C₆-C₁₀ aryloxy, optionally substituted C₆-C₁₀ aryl-S—,        optionally substituted C₇-C₁₄ aralkoxy, optionally substituted        heteroaryl, and optionally substituted heteroaryloxy, optionally        substituted heterocyclyl, optionally substituted        heterocyclyloxy, substituted heterocyclylalkyl, optionally        substituted heterocyclylalkoxy, optionally substituted C₆-C₁₀        aryl-SO₂—, optionally substituted heteroaryl-S—, or —N(R¹)(R²),        wherein R¹ is hydrogen or optionally substituted alkyl, and R²        is chosen from optionally substituted alkyl, optionally        substituted aryl, optionally substituted heteroaryl, optionally        substituted heterocyclyl, optionally substituted cycloalkyl,        optionally substituted cycloalkylalkyl, optionally substituted        aryl-CO—, optionally substituted heteroaryl-CO—, optionally        substituted cycloalkyl-CO—, or optionally substituted alkyl-CO—.

Another embodiment provides the compound, or a stereoisomer orpharmaceutically acceptable salt thereof, of Formula (III), wherein X isO. Another embodiment provides the compound, or a stereoisomer orpharmaceutically acceptable salt thereof, of Formula (III), wherein X isCH₂. Another embodiment provides the compound, or a stereoisomer orpharmaceutically acceptable salt thereof, of Formula (III), wherein eachR⁵, R⁷ and R⁸ is independently chosen from hydrogen, halogen, —OH, —CN,optionally substituted C₁-C₆ alkyl, or optionally substituted C₁-C₆alkoxy.

Another embodiment provides the compound, or a stereoisomer orpharmaceutically acceptable salt thereof, of Formula (III), wherein R⁵is hydrogen. Another embodiment provides the compound, or a stereoisomeror pharmaceutically acceptable salt thereof, of Formula (III), whereinR⁷ is hydrogen. Another embodiment provides the compound, or astereoisomer or pharmaceutically acceptable salt thereof, of Formula(III), wherein R⁸ is hydrogen. Another embodiment provides the compound,or a stereoisomer or pharmaceutically acceptable salt thereof, ofFormula (III), wherein R⁷ and R⁸ are hydrogen. Another embodimentprovides the compound, or a stereoisomer or pharmaceutically acceptablesalt thereof, of Formula (III), wherein R⁶ is not hydrogen.

Another embodiment provides the compound, or a stereoisomer orpharmaceutically acceptable salt thereof, of Formula (III), wherein R⁶is optionally substituted heterocyclyl. Another embodiment provides thecompound, or a stereoisomer or pharmaceutically acceptable salt thereof,of Formula (III), wherein R⁶ is optionally substituted heterocyclyloxy.Another embodiment provides the compound, or a stereoisomer orpharmaceutically acceptable salt thereof, of Formula (III), wherein R⁶is optionally substituted heterocyclylalkyl. Another embodiment providesthe compound, or a stereoisomer or pharmaceutically acceptable saltthereof, of Formula (III), wherein R⁶ is optionally substitutedheterocyclylalkoxy. Another embodiment provides the compound, or astereoisomer or pharmaceutically acceptable salt thereof, of Formula(III), wherein R⁶ is optionally substituted C₆-C₁₀ aryl-SO₂—, oroptionally substituted heteroaryl-S—.

Another embodiment provides the compound, or a stereoisomer orpharmaceutically acceptable salt thereof, of Formula (III), wherein R⁶is —N(R¹)(R²), wherein R¹ is hydrogen and R² is chosen from optionallysubstituted alkyl, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted heterocyclyl, optionally substitutedcycloalkyl, optionally substituted cycloalkylalkyl, optionallysubstituted aryl-CO—, optionally substituted heteroaryl-CO—, optionallysubstituted cycloalkyl-CO—, or optionally substituted alkyl-CO—. Anotherembodiment provides the compound, or a stereoisomer or pharmaceuticallyacceptable salt thereof, of Formula (III), wherein R⁶ is —N(R¹)(R²),wherein R¹ is optionally substituted alkyl and R² is chosen fromoptionally substituted alkyl, optionally substituted aryl, optionallysubstituted heteroaryl, optionally substituted heterocyclyl, optionallysubstituted cycloalkyl, optionally substituted cycloalkylalkyl,optionally substituted aryl-CO—, optionally substituted heteroaryl-CO—,optionally substituted cycloalkyl-CO—, or optionally substitutedalkyl-CO—. Another embodiment provides the compound, or a stereoisomeror pharmaceutically acceptable salt thereof, of Formula (III), whereinR⁶ is —N(R¹)(R²), and R² is optionally substituted alkyl. Anotherembodiment provides the compound, or a stereoisomer or pharmaceuticallyacceptable salt thereof, of Formula (III), wherein R⁶ is —N(R¹)(R²), andR² is optionally substituted aryl. Another embodiment provides thecompound, or a stereoisomer or pharmaceutically acceptable salt thereof,of Formula (III), wherein R⁶ is —N(R¹)(R²), and R² is optionallysubstituted heteroaryl. Another embodiment provides the compound, or astereoisomer or pharmaceutically acceptable salt thereof, of Formula(III), wherein R⁶ is —N(R¹)(R²), and R² is optionally substitutedheterocyclyl. Another embodiment provides the compound, or astereoisomer or pharmaceutically acceptable salt thereof, of Formula(III), wherein R⁶ is —N(R¹)(R²), and R² is optionally substitutedcycloalkyl. Another embodiment provides the compound, or a stereoisomeror pharmaceutically acceptable salt thereof, of Formula (III), whereinR⁶ is —N(R¹)(R²), and R² is optionally substituted cycloalkylalkyl.Another embodiment provides the compound, or a stereoisomer orpharmaceutically acceptable salt thereof, of Formula (III), wherein R⁶is —N(R¹)(R²), and R² is optionally substituted aryl-CO—. Anotherembodiment provides the compound, or a stereoisomer or pharmaceuticallyacceptable salt thereof, of Formula (III), wherein R⁶ is —N(R¹)(R²), andR² is optionally substituted heteroaryl-CO—. Another embodiment providesthe compound, or a stereoisomer or pharmaceutically acceptable saltthereof, of Formula (III), wherein R⁶ is —N(R¹)(R²), and R² isoptionally substituted cycloalkyl-CO—. Another embodiment provides thecompound, or a stereoisomer or pharmaceutically acceptable salt thereof,of Formula (III), wherein R⁶ is —N(R¹)(R²), and R² is optionallysubstituted alkyl-CO—.

One embodiment provides a compound, or a stereoisomer orpharmaceutically acceptable salt thereof, having the structure ofFormula (IV):

wherein,

-   -   X is O or CH₂;    -   R⁶ is an optionally substituted aryl, optionally substituted        heteroaryl, or —N(R¹)(R²), wherein R¹ is hydrogen or optionally        substituted alkyl, and R² is chosen from optionally substituted        aryl or optionally substituted heteroaryl; and    -   each R⁷ and R⁸ is independently chosen from hydrogen, halogen,        —OH, —CN, optionally substituted C₁-C₆ alkyl, or optionally        substituted C₁-C₆ alkoxy.

One embodiment provides a compound, or a stereoisomer orpharmaceutically acceptable salt thereof, having the structure ofFormula (V):

wherein,

-   -   X is O or CH₂;    -   R⁶ is chosen from optionally substituted heterocyclyl,        optionally substituted heterocyclyloxy, optionally substituted        heterocyclylalkyl, optionally substituted heterocyclylalkoxy,        optionally substituted C₆-C₁₀ aryl-SO₂—, optionally substituted        heteroaryl-S—, or —N(R¹)(R²), wherein R¹ is hydrogen or        optionally substituted alkyl, and R² is chosen from optionally        substituted alkyl, optionally substituted aryl, optionally        substituted heteroaryl, optionally substituted heterocyclyl,        optionally substituted cycloalkyl, optionally substituted        cycloalkylalkyl, optionally substituted aryl-CO—, optionally        substituted heteroaryl-CO—, optionally substituted        cycloalkyl-CO—, or optionally substituted alkyl-CO—; and    -   each R⁵, R⁷ and R⁸ is independently chosen from hydrogen,        halogen, —OH, —CN, optionally substituted C₁-C₆ alkyl,        optionally substituted C₁-C₆ alkoxy, optionally substituted        C₃-C₇ carbocyclyl, optionally substituted C₃-C₇ carbocyclyloxy,        optionally substituted C₄-C₁₂ carbocyclylalkyl, optionally        substituted C₄-C₁₂ carbocyclylalkoxy, optionally substituted        C₁-C₆ alkynyl, optionally substituted C₁-C₆ alkenyl, optionally        substituted C₆-C₁₀ aryl, optionally substituted C₆-C₁₀ aryloxy,        optionally substituted C₆-C₁₀ aryl-S—, optionally substituted        C₇-C₁₄ aralkoxy, optionally substituted heteroaryl, and        optionally substituted heteroaryloxy, optionally substituted        heterocyclyl, optionally substituted heterocyclyloxy,        substituted heterocyclylalkyl, optionally substituted        heterocyclylalkoxy, optionally substituted C₆-C₁₀ aryl-SO₂—,        optionally substituted heteroaryl-S—, or —N(R¹)(R²), wherein R¹        is hydrogen or optionally substituted alkyl, and R² is chosen        from optionally substituted alkyl, optionally substituted aryl,        optionally substituted heteroaryl, optionally substituted        heterocyclyl, optionally substituted cycloalkyl, optionally        substituted cycloalkylalkyl, optionally substituted aryl-CO—,        optionally substituted heteroaryl-CO—, optionally substituted        cycloalkyl-CO—, or optionally substituted alkyl-CO—;

with the provision that at least one of R⁵, R⁷ and R⁸ is hydrogen.

Another embodiment provides the compound, or a stereoisomer orpharmaceutically acceptable salt thereof, of Formula (V), wherein X isO. Another embodiment provides the compound, or a stereoisomer orpharmaceutically acceptable salt thereof, of Formula (V), wherein X isCH₂.

Another embodiment provides the compound, or a stereoisomer orpharmaceutically acceptable salt thereof, of Formula (V), wherein R⁵ ishydrogen. Another embodiment provides the compound, or a stereoisomer orpharmaceutically acceptable salt thereof, of Formula (V), wherein R⁷ ishydrogen. Another embodiment provides the compound, or a stereoisomer orpharmaceutically acceptable salt thereof, of Formula (V), wherein R⁸ ishydrogen. Another embodiment provides the compound, or a stereoisomer orpharmaceutically acceptable salt thereof, of Formula (V), wherein R⁵, R⁷and R⁸ are hydrogen.

Another embodiment provides the compound, or a stereoisomer orpharmaceutically acceptable salt thereof, of Formula (V), wherein R⁶ isoptionally substituted heterocyclyl, or optionally substitutedheterocyclyloxy.

Another embodiment provides the compound, or a stereoisomer orpharmaceutically acceptable salt thereof, of Formula (V), wherein R⁶ isoptionally substituted C₆-C₁₀ aryl-SO₂—, or optionally substitutedheteroaryl-S—.

Another embodiment provides the compound, or a stereoisomer orpharmaceutically acceptable salt thereof, of Formula (V), wherein R⁶ is—N(R¹)(R²), wherein R¹ is hydrogen; and R² is chosen from optionallysubstituted alkyl, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted heterocyclyl, optionally substitutedcycloalkyl, optionally substituted cycloalkylalkyl, optionallysubstituted aryl-CO—, optionally substituted heteroaryl-CO—, optionallysubstituted cycloalkyl-CO—, or optionally substituted alkyl-CO—.

Another embodiment provides the compound, or a stereoisomer orpharmaceutically acceptable salt thereof, of Formula (V), wherein R⁶ is—N(R¹)(R²), wherein R¹ is optionally substituted alkyl; and R² is chosenfrom optionally substituted alkyl, optionally substituted aryl,optionally substituted heteroaryl, optionally substituted heterocyclyl,optionally substituted cycloalkyl, optionally substitutedcycloalkylalkyl, optionally substituted aryl-CO—, optionally substitutedheteroaryl-CO—, optionally substituted cycloalkyl-CO—, or optionallysubstituted alkyl-CO—.

Another embodiment provides the compound, or a stereoisomer orpharmaceutically acceptable salt thereof, of Formula (V), wherein R⁵, R⁷and R⁸ are hydrogen; and R⁶ is —N(R¹)(R²), wherein R¹ is optionallysubstituted alkyl; and R² is chosen from optionally substituted alkyl,optionally substituted aryl, optionally substituted heteroaryl,optionally substituted heterocyclyl, optionally substituted cycloalkyl,optionally substituted cycloalkylalkyl, optionally substituted aryl-CO—,optionally substituted heteroaryl-CO—, optionally substitutedcycloalkyl-CO—, or optionally substituted alkyl-CO—. Another embodimentprovides the compound, or a stereoisomer or pharmaceutically acceptablesalt thereof, of Formula (V), wherein R⁵, R⁷ and R⁸ are hydrogen; and R⁶is —N(R¹)(R²), wherein R¹ is optionally substituted alkyl; and R² isoptionally substituted aryl.

Another embodiment provides the compound, or a stereoisomer orpharmaceutically acceptable salt thereof, of Formula (V), wherein R⁵, R⁷and R⁸ are hydrogen; and R⁶ is —N(R¹)(R²), wherein R¹ is optionallysubstituted alkyl; and R² is optionally substituted heteroaryl.

Another embodiment provides the compound, or a stereoisomer orpharmaceutically acceptable salt thereof, of Formula (V), wherein R⁵, R⁷and R⁸ are hydrogen; and R⁶ is —N(R¹)(R²), wherein R¹ is optionallysubstituted alkyl; and R² is optionally substituted heterocyclyl,optionally substituted cycloalkyl, optionally substitutedcycloalkylalkyl, optionally substituted aryl-CO—, optionally substitutedcycloalkyl-CO—, or optionally substituted alkyl-CO—.

Another embodiment provides the compound, or a stereoisomer orpharmaceutically acceptable salt thereof, of Formula (V), wherein R⁵, R⁷and R⁸ are hydrogen; and R⁶ is —N(R¹)(R²), wherein R¹ is optionallysubstituted C1-C3 alkyl; and R² is optionally substituted heterocyclyl,optionally substituted cycloalkyl, optionally substitutedcycloalkylalkyl, optionally substituted aryl-CO—, optionally substitutedcycloalkyl-CO—, or optionally substituted alkyl-CO—.

Another embodiment provides the compound, or a stereoisomer orpharmaceutically acceptable salt thereof, of Formula (V), wherein R⁵, R⁷and R⁸ are hydrogen; and R⁶ is —N(R¹)(R²), wherein R¹ is a CH₃ group;and R² is optionally substituted heterocyclyl, optionally substitutedcycloalkyl, optionally substituted cycloalkylalkyl, optionallysubstituted aryl-CO—, optionally substituted cycloalkyl-CO—, oroptionally substituted alkyl-CO—.

Another embodiment provides the compound, or a stereoisomer orpharmaceutically acceptable salt thereof, of Formula (V), wherein R⁵, R⁷and R⁸ are hydrogen; and R⁶ is —N(R¹)(R²), wherein R¹ is optionallysubstituted alkyl; and R² is an optionally substituted aryl substitutedwith at least one substituent selected from optionally substituted C1-C5alkyl, optionally substituted C2-C5 alkenyl, halogen, cyano, hydroxy,amino, optionally substituted C1-C5 alkoxy, optionally substitutedalkylamino, optionally substituted dialkylamino, optionally substitutedheterocyclyl, optionally substituted heteroaryl, optionally substitutedcycloalkyl, optionally substituted cycloalkylalkyl, optionallysubstituted cycloalkylalkoxy, or optionally substituted cycloalkoxy.

Another embodiment provides the compound, or a stereoisomer orpharmaceutically acceptable salt thereof, of Formula (V), wherein R⁵, R⁷and R⁸ are hydrogen; and R⁶ is —N(R¹)(R²), wherein R¹ is optionallysubstituted alkyl; and R² is an optionally substituted aryl substitutedwith at least one substituent selected from optionally substituted C1-C5alkyl, halogen, optionally substituted C1-C5 alkoxy, optionallysubstituted heterocyclyl, optionally substituted heteroaryl, optionallysubstituted cycloalkyl, optionally substituted cycloalkylalkyl,optionally substituted cycloalkylalkoxy, or optionally substitutedcycloalkoxy.

Another embodiment provides the compound, or a stereoisomer orpharmaceutically acceptable salt thereof, of Formula (V), wherein R⁵, R⁷and R⁸ are hydrogen; and R⁶ is —N(R¹)(R²), wherein R¹ is optionallysubstituted alkyl; and R² is an optionally substituted aryl substitutedwith at least one substituent selected from optionally substitutedheterocyclyl, optionally substituted heteroaryl, optionally substitutedcycloalkyl, optionally substituted cycloalkylalkyl, optionallysubstituted cycloalkylalkoxy, or optionally substituted cycloalkoxy.

Another embodiment provides the compound, or a stereoisomer orpharmaceutically acceptable salt thereof, of Formula (V), wherein R⁵, R⁷and R⁸ are hydrogen; and R⁶ is —N(R¹)(R²), wherein R¹ is optionallysubstituted alkyl; and R² is an optionally substituted aryl substitutedwith at least one substituent selected from optionally substituted C1-C5alkyl, halogen, or optionally substituted C1-C5 alkoxy.

Another embodiment provides the compound, or a stereoisomer orpharmaceutically acceptable salt thereof, of Formula (V), wherein R⁵, R⁷and R⁸ are hydrogen; and R⁶ is —N(R¹)(R²), wherein R¹ is optionallysubstituted alkyl; and R² is an optionally substituted aryl substitutedwith at least one optionally substituted C1-C5 alkyl.

Another embodiment provides the compound, or a stereoisomer orpharmaceutically acceptable salt thereof, of Formula (V), wherein X isO; R⁵, R⁷ and R⁸ are hydrogen; and R⁶ is —N(R¹)(R²), wherein R¹ is a CH₃group; and R² is an optionally substituted aryl substituted with atleast one substituent selected from optionally substituted C1-C5 alkyl,halogen, or optionally substituted C1-C5 alkoxy.

Another embodiment provides the compound, or a stereoisomer orpharmaceutically acceptable salt thereof, of Formula (V), wherein X isCH₂; R⁵, R⁷ and R⁸ are hydrogen; and R⁶ is —N(R¹)(R²), wherein R¹ is aCH₃ group; and R² is an optionally substituted aryl substituted with atleast one substituent selected from optionally substituted C1-C5 alkyl,halogen, or optionally substituted C1-C5 alkoxy.

Another embodiment provides the compound, or a stereoisomer orpharmaceutically acceptable salt thereof, of Formula (V), wherein X isO; R⁵, R⁷ and R⁸ are hydrogen; and R⁶ is —N(R¹)(R²), wherein R¹ is a CH₃group; and R² is an optionally substituted aryl.

Another embodiment provides the compound, or a stereoisomer orpharmaceutically acceptable salt thereof, of Formula (V), wherein X isCH₂; R⁵, R⁷ and R⁸ are hydrogen; and R⁶ is —N(R¹)(R²), wherein R¹ is aCH₃ group; and R² is an optionally substituted aryl.

One embodiment provides a compound, or a stereoisomer orpharmaceutically acceptable salt thereof, chosen from:

One embodiment provides a compound, or a stereoisomer orpharmaceutically acceptable salt thereof, chosen from:

One embodiment provides a compound, or a stereoisomer orpharmaceutically acceptable salt thereof, chosen from:

One embodiment provides a compound, or a stereoisomer orpharmaceutically acceptable salt thereof, chosen from:

In some embodiments, the substituted pyridine derivative compound asdescribed herein, or a stereoisomer or pharmaceutically acceptable saltthereof, has the structure provided in Table 1.

TABLE 1 Chemical Synthesis Example Structure Comments 1

3-({[(1S)-6-[methyl(phenyl)amino]-1,2,3,4- tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 2

3-({[(1S)-6-[methyl(phenyl)amino]-1,2,3,4- tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 3

3-({[6-(2-oxopyrrolidin-1-yl)-1,2,3,4- tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 4

3-({[6-(1,2,3,4-tetrahydroquinolin-1-yl)-1,2,3,4-tetrahydronaphthalen-1- yl]methyl}amino)pyridine-4-carboxylicacid 5

3-({[6-(2,3-dihydro-1H-indol-1-yl)-1,2,3,4- tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 6

3-({[(1R)-6-[(2-fluorophenyl)(methyl)amino]-1,2,3,4-tetrahydronaphthalen-1- yl]methyl}amino)pyridine-4-carboxylicacid 7

3-({[(1R)-6-[(3-fluroophenyl)(methyl)amino]-1,2,3,4-tetrahydronaphthalen-1- yl]methyl}amino)pyridine-4-carboxylicacid 8

3-({[(1R)-6-[(4-fluorophenyl)(methyl)amino]-1,2,3,4-tetrahydronaphthalen-1- yl]methyl}amino)pyridine-4-carboxylicacid 9

3-({[(1R)-6-[(4-chlorophenyl)(methyl)amino]-1,2,3,4-tetrahydronaphthalen-1- yl]methyl}amino)pyridine-4-carboxylicacid 10

3-({[(1R)-6-[ethyl(phenyl)amino]-1,2,3,4- tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 11

3-({[(1R)-6-[methyl(pyridin-2-yl)amino]- 1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 12

3-({[(1R)-6-[methyl(pyridin-3-yl)amino]- 1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 13

3-({[(1R)-6-[(6-methoxypyridin-3- yl)(methyl)amino]-1,2,3,4-tetrahydronaphthalen-1- yl]methyl}amino)pyridine-4-carboxylic acid 14

3-{[(7-bromo-3,4-dihydro-2H-1-benzopyran-4-yl)methyl]amino}pyridine-4-carboxylic acid 15

3-({[7-(phenylamino)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4- carboxylic acid 16

3-({[7-(1,2,3,4-tetrahydroquinolin-1-yl)-3,4- dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic acid 17

3-({[7-(2,3-dihydro-1H-indol-1-yl)-3,4- dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic acid 18

3-({[(4R)-7-[methyl(phenyl)amino]-3,4- dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic acid 19

3-({[(4R)-7-[(2-fluorophenyl)(methyl)amino]-3,4-dihydro-2H-1-benzopyran-4- yl]methyl}amino)pyridine-4-carboxylicacid 20

3-({[(4R)-7-[(3-fluorophenyl)(methyl)amino]-3,4-dihydro-2H-1-benzopyran-4- yl]methyl}amino)pyridine-4-carboxylicacid 21

3-({[(4R)-7-[(4-fluorophenyl)(methyl)amino]-3,4-dihydro-2H-1-benzopyran-4- yl]methyl}amino)pyridine-4-carboxylicacid 22

3-({[(4R)-7-[methyl(4-methylphenyl)amino]-3,4-dihydro-2H-1-benzopyran-4- yl]methyl}amino)pyridine-4-carboxylicacid 23

3-({[(4R)-7-[(4-chlorophenyl)(methyl)amino]-3,4-dihydro-2H-1-benzopyran-4- yl]methyl}amino)pyridine-4-carboxylicacid 24

3-({[(4R)-7-[ethyl(phenyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine- 4-carboxylic acid 25

3-{[(2-phenyl-5,6,7,8-tetrahydroquinolin-5-yl)methyl]amino}pyridine-4-carboxylic acid 26

3-[({2-[methyl(phenyl)amino]-5,6,7,8- tetrahydroquinolin-5-yl}methyl)amino]pyridine-4-carboxylic acid 27

3-[({7-[4-(trifluoromethyl)phenyl]-3,4-dihydro-2H-1-benzopyran-4-yl}methyl)amino]pyridine- 4-carboxylic acid 28

3-({[7-(furan-3-yl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4- carboxylic acid 29

3-({[(4S)-7-(3-methylphenyl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4- carboxylic acid 30

3-({[(4R)-7-(3-methylphenyl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4- carboxylic acid 31

3-({[(4S)-7-(4-methylphenyl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4- carboxylic acid 32

3-({[(4R)-7-(4-methylphenyl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4- carboxylic acid 33

3-({[(4S)-7-(thiophen-3-yl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4- carboxylic acid 34

3-({[(4R)-7-(thiophen-3-yl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4- carboxylic acid 35

3-({[(4R)-7-cyclohexyl-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4- carboxylic acid 36

3-({[(4S)-7-(2-methylthiophen-3-yl)-3,4- dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic acid 37

3-({[(4R)-7-(2-methylthiophen-3-yl)-3,4- dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic acid 38

3-({[7-(3-methylbut-1-yn-1-yl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine- 4-carboxylic acid 39

3-({[(4S)-7-(2-chlorophenyl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4- carboxylic acid 40

3-({[(4R)-7-(2-chlorophenyl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4- carboxylic acid 41

3-({[(4S)-7-(3-fluoro-2-methylphenyl)-3,4- dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic acid 42

3-({[(4R)-7-(3-fluoro-2-methylphenyl)-3,4- dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic acid 43

3-({[(4R)-7-(5-fluoro-2-methylphenyl)-3,4- dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic acid 44

3-({[(4R)-7-(2-chloro-3-fluorophenyl)-3,4- dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic acid 45

3-({[(4R)-7-(2-chloro-5-fluorophenyl)-3,4- dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic acid 46

3-({[(4R)-7-[2-(trifluoromethyl)phenyl]-3,4- dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic acid 47

3-({[(4S)-7-phenoxy-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4- carboxylic acid 48

3-({[(4R)-7-phenoxy-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4- carboxylic acid 49

3-({[7-(thiophen-2-ylsulfanyl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4- carboxylic acid 50

3-({[(4S)-7-[(2-methylphenyl)sulfanyl]-3,4- dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic acid 51

3-({[(4R)-7-[(2-methylphenyl)sulfanyl]-3,4- dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic acid 52

3-({[(4S)-7-[(3-fluorophenyl)sulfanyl]-3,4- dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic acid 53

3-({[(4R)-7-[(3-fluorophenyl)sulfanyl]-3,4- dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic acid 54

3-({[(4S)-7-[(4-fluorophenyl)sulfanyl]-3,4- dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic acid 55

3-({[(4R)-7-[(4-fluorophenyl)sulfanyl]-3,4- dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic acid 56

3-[({6-[(6-methylpyridin-2-yl)oxy]-1,2,3,4- tetrahydronaphthalen-1-yl}methyl)amino]pyridine-4-carboxylic acid 57

3-({[(1S)-6-(2-methylphenoxy)-1,2,3,4- tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 58

3-({[(1R)-6-(2-methylphenoxy)-1,2,3,4- tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 59

3-{[(6-propoxy-1,2,3,4-tetrahydronaphthalen-1-yl)methyl]amino}pyridine-4-carboxylic acid 60

3-({[(1S)-6-(difluoromethoxy)-1,2,3,4- tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 61

3-({[(1R)-6-(difluoromethoxy)-1,2,3,4- tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 62

3-[({6-[2-(trifluoromethyl)phenoxy]-1,2,3,4- tetrahydronaphthalen-1-yl}methyl)amino]pyridine-4-carboxylic acid 63

3-({[6-(oxan-4-ylmethoxy)-1,2,3,4- tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 64

3-({[(1R)-6-(4-fluoro-2-methylphenoxy)- 1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 65

3-({[(1R)-6-(2,4-difluorophenoxy)-1,2,3,4- tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 66

3-({[(1R)-6-(2-fluoro-4-methylphenoxy)- 1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 67

3-({[(1R)-6-(2-chlorophenoxy)-1,2,3,4- tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 68

3-({[(1R)-6-[(3-methylphenyl)sulfanyl]-1,2,3,4- tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 69

3-({[(1R)-6-[(3-methylphenyl)sulfanyl]- 1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 70

3-({[(1S)-6-[(2-methylphenyl)sulfanyl]-1,2,3,4- tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 71

3-({[(1R)-6-[(2-methylphenyl)sulfanyl]- 1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 72

3-({[(1S)-6-[(2-fluoropehnyl)sulfanyl]-1,2,3,4- tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 73

3-({[(1R)-6-[(2-fluoropehnyl)sulfanyl]-1,2,3,4- tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 74

3-({[(1S)-6-[(3-fluorophenyl)sulfanyl]-1,2,3,4- tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 75

3-({[(1R)-6-[(3-fluorophenyl)sulfanyl]-1,2,3,4- tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 76

3-({[(1S)-6-[(4-fluorophenyl)sulfanyl]-1,2,3,4- tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 77

3-({[(1R)-6-[(4-fluorophenyl)sulfanyl]-1,2,3,4- tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 78

3-({[(1S)-6-[(4-methylphenyl)sulfanyl]-1,2,3,4- tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 79

3-({[(1R)-6-[(4-methylphenyl)sulfamyl]- 1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 80

3-({[6-(pyridin-2-ylsulfanyl)-1,2,3,4- tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 81

3-({[(1S)-6-(benzenesulfonyl)-1,2,3,4- tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 82

3-({[(1R)-6-(benzenesulfonyl)-1,2,3,4- tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 83

3-({[(1S)-6-(4-methylbenzenesulfonyl)-1,2,3,4- tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 84

3-({[(1R)-6-(4-methylbenzenesulfonyl)-1,2,3,4- tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 85

3-({[(1S)-6-(3-methylbenzenesulfonyl)-1,2,3,4- tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 86

3-({[(1R)-6-(3-methylbenzenesulfonyl)-1,2,3,4- tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 87

3-({[6-(3-fluorobenzenesulfonyl)-1,2,3,4- tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 88

3-({[6-(oxan-4-yl)-1,2,3,4- tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 89

3-({[6-(2-methylpyridin-4-yl)-1,2,3,4- tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid, hydrochloride 90

3-({[(1S)-6-ethyl-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 91

3-({[(1R)-6-ethyl-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 92

3-({2H,3H,6H,7H,8H,9H-naphtho[1,2-b]furan-6-ylmethyl}amino)pyridine-4-carboxylic acid 93

3-{[(6,7-dimethyl-3,4-dihydro-2H-1-benzopyran-4-yl)methyl]amino}pyridine-4- carboxylic acid 94

3-{[(6-methoxy-7-methyl-1,2,3,4- tetrahydronaphthalen-1-yl)methyl]amino}pyridine-4-carboxylic acid 95

3-{[(6,8-dimethoxy-1,2,3,4- tetrahydronaphthalen-1-yl)methyl]amino}pyridine-4-carboxylic acid 96

3-({[(1S)-7-fluoro-6-methoxy-1,2,3,4- tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 97

3-({[(1R)-7-fluoro-6-methoxy-1,2,3,4- tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 98

3-({[(1S)-6-methoxy-5-methyl-1,2,3,4- tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 99

3-({[(1R)-6-methoxy-5-methyl-1,2,3,4- tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 100

3-({[(4S)-7-(2-methylphenyl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4- carboxylic acid 101

3-({[(4R)-7-(2-methylphenyl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4- carboxylic acid 102

3-({[(4R)-7-(5-fluoro-2-methoxyphenyl)-3,4- dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic acid 103

3-({[(1R)-6-[(4-cyanophenyl)(methyl)amino]-1,2,3,4-tetrahydronaphthalen-1- yl]methyl}amino)pyridine-4-carboxylicacid 104

3-({[(4R)-7-[(2,4- difluorophenyl)(methyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine- 4-carboxylic acid 105

3-({[(4R)-7-[methyl(3-methylphenyl)amino]-3,4-dihydro-2H-1-benzopyran-4- yl]methyl}amino)pyridine-4-carboxylicacid 106

3-({[(1R)-6-(pyrrolidin-1-yl)-1,2,3,4- tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 107

3-({[(4R)-7-(2-chloro-5-methoxyphenyl)-3,4- dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic acid 108

3-({[(1R)-6-(3,4-dihydro-2H-1,4-benzoxazin-4-yl)-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 109

3-({[(4R)-7-[(3,5- difluorophenyl)(methyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine- 4-carboxylic acid 110

3-({[(4R)-7-[(3-chlorophenyl)(methyl)amino]-3,4-dihydro-2H-1-benzopyran-4- yl]methyl}amino)pyridine-4-carboxylicacid 111

3-({[(4R)-7-[methyl(2-methylphenyl)amino]-3,4-dihydro-2H-1-benzopyran-4- yl]methyl}amino)pyridine-4-carboxylicacid 112

3-({[(4R)-7-[(4-fluoro-3- methoxyphenyl)(methyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine- 4-carboxylic acid 113

3-({[(1R)-6-[methyl(oxan-4-yl)amino]-1,2,3,4- tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 114

3-({[(1R)-6-[(4-fluoro-3- methoxyphenyl)(methyl)amino]-1,2,3,4-tetrahydronaphthalen-1- yl]methyl}amino)pyridine-4-carboxylic acid 115

3-({[(1R)-6-[(3-cyanophenyl)(methyl)amino]-1,2,3,4-tetrahydronaphthalen-1- yl]methyl}amino)pyridine-4-carboxylicacid 116

3-({[(4R)-7-(2-methoxyphenyl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine- 4-carboxylic acid 117

3-({[(4R)-7-[(3-cyanophenyl)(methyl)amino]-3,4-dihydro-2H-1-benzopyran-4- yl]methyl}amino)pyridine-4-carboxylicacid 118

3-({[(4R)-7-(4-fluoro-2-methoxyphenyl)-3,4- dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic acid 119

3-({[(4R)-7-[(4-cyanophenyl)(methyl)amino]-3,4-dihydro-2H-1-benzopyran-4- yl]methyl}amino)pyridine-4-carboxylicacid 120

3-({[(1R)-6- [(cyclopropylmethyl)(methyl)amino]-1,2,3,4-tetrahydronaphthalen-1- yl]methyl}amino)pyridine-4-carboxylic acid 121

3-({[(1R)-6-[methyl(6-methoxypyridin-2-yl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 122

3-({[(1R)-6-[methyl(5-methylpyridin-2-yl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 123

3-({[(1R)-6-[methyl(6-methylpyridin-2-yl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 124

3-({[(4R)-7-(2-cyanophenyl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4- carboxylic acid 125

3-({[(1R)-6-[methyl(1-methyl-1H-pyrazol-3-yl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 126

3-({[(4)R-7-[(4-ethynylphenyl)(methyl)amino]-3,4-dihydro-2H-1-benzopyran-4- yl]methyl}amino)pyridine-4-carboxylicacid 127

3-({[(4R)-7-[(1,3-dihydro-2-benzofuran-5-yl)(methyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4- carboxylic acid 128

3-({[(4R)-7-{methyl[4- (trifluoromethyl)phenyl]amino}-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine- 4-carboxylic acid 129

3-[({7-[phenyl(2,2,2-trifluoroethyl)amino]-3,4-dihydro-2H-1-benzopyran-4- yl}methyl)amino]pyridine-4-carboxylic acid130

3-({[(1R)-6-[benzyl(methyl)amino]-1,2,3,4- tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 131

3-({[(4R)-7-[(2,3-dihydro-1H-inden-5-yl)(methyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4- carboxylic acid 132

3-({[(1R)-6-[(1,3-dihydro-2-benzofuran-5- yl)(methyl)amino]-1,2,3,4-tetrahydronaphthalen-1- yl]methyl}amino)pyridine-4-carboxylic acid 133

3-({[(1R)-6-[cyclopentyl(methyl)amino]- 1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 134

3-({[(4R)-7-[(4- cyclopropylphenyl)(methyl)amino]-3,4-dihydro-2H-1-benzopyran-4- yl]methyl}amino)pyridine-4-carboxylic acid135

3-({[(1R)-6-[(1-benzofuran-6- yl)(methyl)amino]-1,2,3,4-tetrahydronaphthalen-1- yl]methyl}amino)pyridine-4-carboxylic acid 136

3-({[(4R)-7-[(1-benzofuran-5- yl)(methyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4- carboxylic acid 137

3-({[(1R)-6-[(1-benzofuran-5- yl)(methyl)amino]-1,2,3,4-tetrahydronaphthalen-1- yl]methyl}amino)pyridine-4-carboxylic acid 138

3-({[(4R)-7-(2-hydroxyphenyl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine- 4-carboxylic acid 139

3-({[(4R)-7-[methyl(2-methyl-1,3-thiazol-4-yl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic acid 140

3-({[(1R)-6-[methyl(4-methylphenyl)amino]-1,2,3,4-tetrahydronaphthalen-1- yl]methyl}amino)pyridine-4-carboxylicacid 141

3-({[(4R)-7-[(1-benzofuran-6- yl)(methyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4- carboxylic acid 142

3-[(3,4-dihydro-1H-2-benzopyran-1- ylmethyl)amino]pyridine-4-carboxylicacid 143

3-({[(1R)-6-[methyl(3-methylphenyl)amino]-1,2,3,4-tetrahydronaphthalen-1- yl]methyl}amino)pyridine-4-carboxylicacid 144

3-({[(1R)-6-[methyl(thiophen-2-yl)amino]-1,2,3,4-tetrahydronaphthalen-1- yl]methyl}amino)pyridine-4-carboxylicacid 145

3-({[(4R)-7-[methyl(5-methylpyridin-2-yl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic acid 146

3-[({6-[methyl(phenyl)amino]-3,4-dihydro-1H-2-benzopyran-1-yl}methyl)amino]pyridine-4- carboxylic acid 147

3-({[(1R)-6-[(2-hydroxyethyl)(phenyl)amino]-1,2,3,4-tetrahydronaphthalen-1- yl]methyl}amino)pyridine-4-carboxylicacid 148

3-({[(4R)-7-[methyl(6-methylpyridin-2-yl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic acid 149

3-[(1,2,3,4-tetrahydroisoquinolin-1-ylmethyl)amino]pyridine-4-carboxylic acid 150

3-({[(1R)-6-[(3- methoxyphenyl)(methyl)amino]-1,2,3,4-tetrahydronaphthalen-1- yl]methyl}amino)pyridine-4-carboxylic acid 151

3-({[(4R)-7-[(3-fluoro-4- methylphenyl)(methyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4- carboxylic acid 152

3-({[(4R)-7-[(5-chloropyridin-2- yl)(methyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4- carboxylic acid 153

3-({[(4R)-7-[(5-cyclopropylpyridin-2-yl)(methyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4- carboxylic acid 154

3-({[(4R)-7-[(4-ethylphenyl)(methyl)amino]-3,4-dihydro-2H-1-benzopyran-4- yl]methyl}amino)pyridine-4-carboxylicacid 155

3-({[(1R)-6-[methyl(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)amino]-1,2,3,4- tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 156

3-({[(1R)-6-[methyl(5-methylpyrimidin-2-yl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 157

3-({[(4R)-7-[(5-ethylpyridin-2- yl)(methyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4- carboxylic acid 158

3-({[(1R)-6-{[4- (hydroxymethyl)phenyl](methyl)amino}-1,2,3,4-tetrahydronaphthalen-1- yl]methyl}amino)pyridine-4-carboxylicacid 159

3-({[(1R)-6-[methyl(1-methyl-1H-pyrazol-4-yl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 160

3-({[(1R)-6-{[4- (dimethylamino)phenyl](methyl)amino}-1,2,3,4-tetrahydronaphthalen-1- yl]methyl}amino)pyridine-4-carboxylicacid 161

3-({[(1R)-6-[(4- cyclopropylphenyl)(methyl)amino]-1,2,3,4-tetrahydronaphthalen-1- yl]methyl}amino)pyridine-4-carboxylic acid 162

3-({[(1R)-6-(2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 163

3-({[(1R)-6-[(4-cyclopropylphenyl)(2- methoxyethyl)amino]-1,2,3,4-tetrahydronaphthalen-1- yl]methyl}amino)pyridine-4-carboxylic acid 164

3-({[(1R)-6-{[4- (methoxymethyl)phenyl](methyl)amino}-1,2,3,4-tetrahydronaphthalen-1- yl]methyl}amino)pyridine-4-carboxylicacid 165

3-({[(1R)-6-[(4- hydroxyphenyl)(methyl)amino]-1,2,3,4-tetrahydronaphthalen-1- yl]methyl}amino)pyridine-4-carboxylic acid 166

3-({[(1R)-6-[(dimethyl-1,2-oxazol-4- yl)(methyl)amino]-1,2,3,4-tetrahydronaphthalen-1- yl]methyl}amino)pyridine-4-carboxylic acid 167

3-({[(1R)-6-{methyl[4-(pyrrolidin-1- yl)phenyl]amino}-1,2,3,4-tetrahydronaphthalen-1- yl]methyl}amino)pyridine-4-carboxylic acid 168

3-({[(1R)-6-({4-[(1R)-1- hydroxyethyl]phenyl}(methyl)amino)-1,2,3,4-tetrahydronaphthalen-1- yl]methyl}amino)pyridine-4-carboxylic acid 169

3-({[(1R)-6-({4-[(1S)-1- hydroxyethyl]phenyl}(methyl)amino)-1,2,3,4-tetrahydronaphthalen-1- yl]methyl}amino)pyridine-4-carboxylic acid 170

3-({[(1R)-6-{methyl[4-(morpholin-4- yl)phenyl]amino}-1,2,3,4-tetrahydronaphthalen-1- yl]methyl}amino)pyridine-4-carboxylic acid 171

3-({[(1R)-6-[methyl(5-methyl-1,2-oxazol-3-yl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 172

3-({[1R)-6-[(2- methoxyphenyl)(methyl)amino]-1,2,3,4-tetrahydronaphthalen-1- yl]methyl}amino)pyridine-4-carboxylic acid 173

3-({[(1R)-6-[methyl(pyridin-4-yl)amino]- 1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 174

3-({[(1R)-6-{[4-(3,6-dihydro-2H-pyran-4-yl)phenyl](methyl)amino}-1,2,3,4- tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 175

3-({[(1R)-6-{methyl[4-(oxan-4- yl)phenyl]amino}-1,2,3,4-tetrahydronaphthalen-1- yl]methyl}amino)pyridine-4-carboxylic acid 176

3-({[(4R)-7-[(4-ethenylphenyl)(methyl)amino]-3,4-dihydro-2H-1-benzopyran-4- yl]methyl}amino)pyridine-4-carboxylicacid 177

3-({[(1R)-6-[(4- methoxyphenyl)(methyl)amino]-1,2,3,4-tetrahydronaphthalen-1- yl]methyl}amino)pyridine-4-carboxylic acid 178

3-({[(4R)-7-[(4- methxoyphenyl)(methyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine- 4-carboxylic acid 179

3-({[(4R)-7-{methyl[4-(pyrrolidin-1- yl)phenyl]amino}-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4- carboxylic acid 180

3-({[(1R)-6-{[4-(azetidin-1- yl)phenyl](methyl)amino}-1,2,3,4-tetrahydronaphthalen-1- yl]methyl}amino)pyridine-4-carboxylic acid 181

3-({[(1R)-6-{methyl[4- (trifluoromethoxy)phenyl]amino}-1,2,3,4-tetrahydronaphthalen-1- yl]methyl}amino)pyridine-4-carboxylic acid 182

3-({[(4R)-7-{methyl[4- (trifluoromethoxy)phenyl]amino}-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine- 4-carboxylic acid 183

3-({[(4R)-7-{[4-(azetidin-1- yl)phenyl](methyl)amino}3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4- carboxylic acid 184

3-({[(1R)-6-{[4- (difluoromethoxy)phenyl](methyl)amino}-1,2,3,4-tetrahydronaphthalen-1- yl]methyl}amino)pyridine-4-carboxylicacid 185

3-({[(1R)-6-[(4-ethoxyphenyl)(methyl)amino]-1,2,3,4-tetrahydronaphthalen-1- yl]methyl}amino)pyridine-4-carboxylicacid 186

3-({[(4R)-7-[(4-ethoxyphenyl)(methyl)amino]-3,4-dihydro-2H-1-benzopyran-4- yl]methyl}amino)pyridine-4-carboxylicacid 187

3-({[(4R)-7-{methyl[4-(propan-2- yl)phenyl]amino}-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4- carboxylic acid 188

3-({[(1R)-6-{methyl[4-(1H-pyrazol-1- yl)phenyl]amino}-1,2,3,4-tetrahydronaphthalen-1- yl]methyl}amino)pyridine-4-carboxylic acid 189

3-({[(4R)-7-{methyl[4-(1H-pyrazol-1- yl)phenyl]amino}-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4- carboxylic acid 190

3-({[(4R)-7-{[4- (difluoromethoxy)phenyl](methyl)amino}-3,4-dihydro-2H-1-benzopyran-4- yl]methyl}amino)pyridine-4-carboxylic acid191

3-({[(1R)-6-[methyl(phenyl)amino]-1,2,3,4- tetrahydronaphthalen-1-yl]methyl}amino)pyridazine-4-carboxylic acid 192

3-({[(4R)-7-{methyl[4-(2,2,2-trifluoroethyl)phenyl]amino}-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4- carboxylic acid 193

3-({[(1R)-6-{[4-(1H-imidazol-1- yl)phenyl](methyl)amino}-1,2,3,4-tetrahydronaphthalen-1- yl]methyl}amino)pyridine-4-carboxylic acid 194

3-({[(4R)-7-{[4-(1H-imidazol-1-yl)phenyl](methyl)amino}-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4- carboxylic acid 195

3-({[(1R)-6-{[4-(3,3-difluoroazetidin-1-yl)phenyl](methyl)amino]-1,2,3,4- tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 196

3-({[(4R)-7-{[4-(3,3-difluoroazetidin-1-yl)phenyl](methyl)amino}-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4- carboxylic acid 197

3-({[(1R)-6-{[4-(2- methoxyethoxy)phenyl](methyl)amino}-1,2,3,4-tetrahydronaphthalen-1- yl]methyl}amino)pyridine-4-carboxylicacid 198

3-({[(4R)-7-(1-phenylethyl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4- carboxylic acid 199

3-({[(4R)-7-{methyl[5-(propan-2-yl)pyridin-2-yl]amino}-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic acid 200

3-({[(1R)-6-{[4-(3-hydroxyazetidin-1- yl)phenyl](methyl)amino}-1,2,3,4-tetrahydronaphthalen-1- yl]methyl}amino)pyridine-4-carboxylic acid 201

3-({[(4R)-7-{[4-(3,6-dihydro-2H-pyran-4-yl)phenyl](methyl)amino}-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4- carboxylic acid 202

3-({[(4R)-7-{methyl[4-(oxan-4- yl)phenyl]amino}-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4- carboxylic acid 203

3-({[(4R)-7-(1-phenylcyclopropyl)-3,4- dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic acid 204

3-({[(4R)-7-{methyl[4-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl]amino}-3,4- dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic acid 205

3-({[(4R)-7-{methyl[4-(1-methylpiperidin-4-yl)phenyl]amino}-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4- carboxylic acid 206

3-({[(4R)-7-[(3,4- dimethylphenyl)(methyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine- 4-carboxylic acid 207

3-({[(4R)-7-{[4-(2- hydroxyethyl)phenyl](methyl)amino}-3,4-dihydro-2H-1-benzopyran-4- yl]methyl}amino)pyridine-4-carboxylic acid208

3-({[(4R)-7-[methyl(4-propylphenyl)amino]-3,4-dihydro-2H-1-benzopyran-4- yl]methyl}amino)pyridine-4-carboxylicacid 209

3-({[(1R)-6-{[4- (cyclopropylmethoxy)phenyl](methyl)amino}-1,2,3,4-tetrahydronaphthalen-1- yl]methyl}amino)pyridine-4-carboxylicacid 210

3-({[(4R)-7-{methyl[4-(propan-2- yloxy)phenyl]amino}-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4- carboxylic acid 211

3-({[(4R)-7-{[4- (cyclopropylmethoxy)phenyl](methyl)amino}-3,4-dihydro-2H-1-benzopyran-4- yl]methyl}amino)pyridine-4-carboxylicacid 212

3-({[(4R)-7-[methyl(4-propoxyphenyl)amino]-3,4-dihydro-2H-1-benzopyran-4- yl]methyl}amino)pyridine-4-carboxylicacid 213

3-({[(4R)-7-[(4- cyclopropoxyphenyl)(methyl)amino]-3,4-dihydro-2H-1-benzopyran-4- yl]methyl}amino)pyridine-4-carboxylic acid214

3-({[(4R)-7-{methyl[4-(2,2,2- trifluoroethoxy)phenyl]amino}-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine- 4-carboxylic acid 215

3-({[(4R)-7-{[4- (cyclopropylmethyl)phenyl](methyl)amino}-3,4-dihydro-2H-1-benzopyran-4- yl]methyl}amino)pyridine-4-carboxylicacid 216

3-({[(4R)-7-[(4- cyclopropanecarbonylphenyl)(methyl)amino]-3,4-dihydro-2H-1-benzopyran-4- yl]methyl}amino)pyridine-4-carboxylicacid 217

3-({[(1S)-5-[methyl(phenyl)amino]-2,3- dihydro-1H-inden-1-yl]methyl}amino)pyridine-4-carboxylic acid 218

3-({[(1R)-5-[methyl(phenyl)amino]-2,3- dihydro-1H-inden-1-yl]methyl}amino)pyridine-4-carboxylic acid 219

3-({[(1S)-5-[methyl(4-methylphenyl)amino]- 2,3-dihydro-1H-inden-1-yl]methyl}amino)pyridine-4-carboxylic acid 220

3-({[(1R)-5-[methyl(4-methylphenyl)amino]- 2,3-dihydro-1H-inden-1-yl]methyl}amino)pyridine-4-carboxylic acid 221

3-({[(1S)-5-{[4- (dimethylamino)phenyl](methyl)amino}-2,3-dihydro-1H-inden-1- yl]methyl}amino)pyridine-4-carboxylic acid 222

3-({[(1R)-5-{[4- (dimethylamino)phenyl](methyl)amino}-2,3-dihydro-1H-inden-1- yl]methyl}amino)pyridine-4-carboxylic acid 223

3-({[(1S)-5-[(4- cyclopropylphenyl)(methyl)amino]-2,3-dihydro-1H-inden-1- yl]methyl}amino)pyridine-4-carboxylic acid 224

3-({[(1R)-5-[(4- cyclopropylphenyl)(methyl)amino]-2,3-dihydro-1H-inden-1- yl]methyl}amino)pyridine-4-carboxylic acid 225

3-({[(3S)-6-[methyl(4-methylphenyl)amino]- 2,3-dihydro-1-benzofuran-3-yl]methyl}amino)pyridine-4-carboxylic acid 226

3-({[(3R)-6-[methyl(4-methylphenyl)amino]- 2,3-dihydro-1-benzofuran-3-yl]methyl}amino)pyridine-4-carboxylic acid 227

3-({[(3S)-6-[(4- cyclopropylphenyl)(methyl)amino]-2,3-dihydro-1-benzofuran-3- yl]methyl}amino)pyridine-4-carboxylic acid 228

3-({[(3R)-6-[(4- cyclopropylphenyl)(methyl)amino]-2,3-dihydro-1-benzofuran-3- yl]methyl}amino)pyridine-4-carboxylic acid 229

3-({[(1S)-5-[methyl(4-methylphenyl)amino]- 1,3-dihydro-2-benzofuran-2-yl]methyl}amino)pyridine-4-carboxylic acid 230

3-({[(1R)-5-[methyl(4-methylphenyl)amino]- 1,3-dihydro-2-benzofuran-1-yl]methyl}amino)pyridine-4-carboxylic acid 231

3-({[(1R)-5-[methyl(3-methylphenyl)amino]- 2,3-dihydro-1H-inden-1-yl]methyl}amino)pyridine-4-carboxylic acid 231

3-({[(1R)-5-[(4-ethylphenyl)(methyl)amino]- 2,3-dihydro-1H-inden-1-yl]methyl}amino)pyridine-4-carboxylic acid 232

3-({[(1R)-5-{methyl[4-(pyrrolidin-1-yl)phenyl]amino}-2,3-dihydro-1H-inden-1-yl]methyl}amino)pyridine-4-carboxylic acid

In some embodiments, the substituted pyridine derivative compound asdescribed herein, or a stereoisomer or pharmaceutically acceptable saltthereof, has the structure provided in Table 2.

TABLE 2

3-({[(4S)-7-(thiophen-2-yl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic acid

3-({[(1R)-6-(N-methylbenzamido)-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4- carboxylic acid

3-({[(1R)-6-(N-methylcyclopropaneamido)-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4- carboxylic acid

3-({[((1R)-6-(N-methylcyclopentaneamido)-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4- carboxylic acid

3-({[(1R)-6-(dimethylamino)-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4- carboxylic acid

3-({[(4S)-7-[1-(cyclopropylmethyl)-1H-pyrazol-4-yl]-3,4-dihydro-2H-1-benzopyran-4- yl]methyl}amino)pyridine-4-carboxylicacid

3-({[(1R)-6-[methyl(1-methyl-1H-pyrazol-3-yl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid

3-({[(1R)-6-[benzyl(methyl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4- carboxylic acid

3-({[(4S)-7-(5-methylthiophen-2-yl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4- carboxylic acid

3-({[(4S)-7-(4-cyanophenyl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic acid

3-({[(4S)-7-(2-cyclopentylethynyl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic acid

3-({[(4S)-7-(3,6-dihydro-2H-pyran-4-yl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4- carboxylic acid

3-({[(4S)-7-(4-methoxyphenyl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic acid

3-({[(4S)-7-[1-(cyclopropylmethyl)-1H-pyrazol-3-yl]-3,4-dihydro-2H-1-benzopyran-4- yl]methyl}amino)pyridine-4-carboxylicacid

3-({[(4S)-7-(pyridin-2-yl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic acid

3-({[(4S)-7-(pyridin-3-yl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic acid

3-({[(4S)-7-(2-methyl-1,3-thiazol-5-yl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4- carboxylic acid

3-({[(4S)-7-(2-methyl-1,3-thiazol-4-yl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4- carboxylic acid

3-({[(4S)-7-(1,2,3,6-tetrahydropyridin-4-yl)-3,4-dihydro-2H-1-benzopyran-4- yl]methyl}amino)pyridine-4-carboxylic acid

3-({[(4S)-7-(piperidin-4-yl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic acid

3-({[(4S)-7-(oxan-4-yl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic acid

3-({[(4S)-742-(1-hydroxycyclopentyl)ethynyl]-3,4-dihydro-2H-1-benzopyran-4- yl]methyl}amino)pyridine-4-carboxylic acid

3-({[(4S)-7-(2-cyanophenyl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic acid

3-({[(4S)-7-(3-cyanophenyl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic acid

3-({[(4S)-7-(4-cyano-2-fluorophenyl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4- carboxylic acid

3-({[(4S)-7-(4-cyano-3-fluorophenyl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4- carboxylic acid

3-({[(4S)-7-[4-(trifluoromethoxy)phenyl]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4- carboxylic acid

3-({[(4S)-7-(4-chlorophenyl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic acid

3-({[(4S)-7-(2-chloro-4-cyanophenyl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4- carboxylic acid

3-({[(4S)-7-(3-chloro-4-cyanophenyl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4- carboxylic acid

3-({[(4S)-7-(2,4-difluorophenyl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic acid

3-({[(4S)-7-(5-chlorothiophen-3-yl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4- carboxylic acid

3-({[(4S)-7-(5-cyanothiophen-3-yl)-3,4-dihydro-2H-1-dihydro-2H-1-benzopyran-4- yl]methyl}amino)pyridine-4-carboxylic acid

3-({[(4S)-7-[5-(cyanothiophen-3-yl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic acid

3-({[(4S)-7-(5-chlorothiophen-2-yl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4- carboxylic acid

3-({[(4S)-7-[5-(trifluoromethyl)thiophen-2-yl]-3,4-dihydro-2H-1-benzopyran-4- yl]methyl}amino)pyridine-4-carboxylic acid

3-({[(4S)-7-(5-cyanothiophen-2-yl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic acid

3-({[(3S)-6-[1-(cyclopropylmethyl)-1H-pyrazol-4-yl]-2,3-dihydro-1-benzofuran-3- yl]methyl}amino)pyridine-4-carboxylic acid

3-({[(1R)-5-{methyl[4-(morpholin-4-yl)phenyl]amino}-2,3-dihydro-1H-inden-1-yl]methyl}amino)pyridine-4-carboxylic acid

3-({[(1R)-5-{[4-(3,3-difluoroazetidin-1-yl)phenyl](methyl)amino}-2,3-dihydro-1H-inden-1-yl]methyl}amino)pyridine-4-carboxylic acid

3-({[(1R)-5-[(4-methoxyphenyl)(methyl)amino]-2,3-dihydro-1H-inden-1-yl]methyl}amino)pyridine-4- carboxylic acid

3-({[(1R)-5-[(4-methoxyphenyl)(methyl)amino]-2,3-dihydro-1H-inden-1-yl]methyl}amino)pyridine-4- carboxylic acid

3-({[(1R)-5-[(3-methoxyphenyl)(methyl)amino]-2,3-dihydro-1H-inden-1-yl]methyl}amino)pyridine-4- carboxylic acid

3-({[(1R)-5-{[4-(azetidin-1-yl)phenyl](methyl)amino}-2,3-dihydro-1H-inden-1-yl]methyl}amino)pyridine-4-carboxylic acid

3-({[(1R)-5-{[3- (difluoromethoxy)phenyl](methyl)amino}-2,3-dihydro-1H-inden-1-yl]methyl}amino)pyridine-4- carboxylic acid

3-({[(1R)-5-[(3-ethoxyphenyl)(methyl)amino]-2,3-dihydro-1H-inden-1-yl]methyl}amino)pyridine-4- carboxylic acid

3-({[(1R)-5-{methyl[4-(propan-2-yl)phenyl]amino}-2,3-dihydro-1H-inden-1-yl]methyl}amino)pyridine-4- carboxylic acid

3-({[(1R)-5-{methyl[5-(propan-2-yl)pyridin-2-yl]amino}-2,3-dihydro-1H-inden-1- yl]methyl}amino)pyridine-4-carboxylicacid

3-({[(1R)-5-[methyl(pyridin-2-yl)amino]-2,3-dihydro-1H-inden-1-yl]methyl}amino)pyridine-4-carboxylic acid

3-({[(1R)-5-[(6-methoxypyridin-2-yl)(methyl)amino]-2,3-dihydro-1H-inden-1-yl]methyl}amino)pyridine-4- carboxylic acid

3-({[(1R)-5-[(2,3-dihydro-1,4-benzodioxin-6-yl)(methyl)amino]-2,3-dihydro-1H-inden-1-yl]methyl}amino)pyridine-4-carboxylic acid

3-({[(1R)-5-[methyl(pyrimidin-4-yl)amino]-2,3-dihydro-1H-inden-1-yl]methyl}amino)pyridine-4- carboxylic acid

3-({[(1R)-5-{[4-(3,6-dihydro-2H-pyran-4-yl)phenyl](methyl)amino}-2,3-dihydro-1H-inden-1-yl]methyl}amino)pyridine-4-carboxylic acid

3-({[(1R)-5-{methyl[4-(oxan-4-yl)phenyl]amino}-2,3-dihydro-1H-inden-1-yl]methyl}amino)pyridine-4- carboxylic acid

3-({[(1R)-5-{methyl[4-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl]amino}-2,3-dihydro-1H-inden-1-yl]methyl}amino)pyridine-4-carboxylic acid

3-({[(1R)-5-{methyl[4-(1-methylpiperidin-4-yl)phenyl]amino}-2,3-dihydro-1H-inden-1-yl]methyl}amino)pyridine-4-carboxylic acid

3-({[(1R)-5-[methyl(5-methylpyridin-2-yl)amino]-2,3-dihydro-1H-inden-1-yl]methyl}amino)pyridine-4- carboxylic acid

3-({[(1R)-5-[(5-ethylpyridin-2-yl)(methyl)amino]-2,3-dihydro-1H-inden-1-yl]methyl}amino)pyridine-4- carboxylic acid

3-({[(1R)-5-{[4-(3-hydroxyazetidin-1-yl)phenyl](methyl)amino}-2,3-dihydro-1H-inden-1-yl]methyl}amino)pyridine-4-carboxylic acid

3-({[(1R)-5-{methyl[4-(propan-2-yloxy)phenyl]amino}-2,3-dihydro-1H-inden-1-yl]methyl}amino)pyridine-4-carboxylic acid

3-({[(1R)-5-{[4- (cyclopropylmethoxy)phenyl](methyl)amino}-2,3-dihydro-1H-inden-1-yl]methyl}amino)pyridine-4- carboxylic acid

3-({[(1R)-5-{methyl[4-(2,2,2-trifluoroethoxy)phenyl]amino}-2,3-dihydro-1H-inden-1-yl]methyl}amino)pyridine-4-carboxylic acid

3-({[(1R)-5-[methyl(4-propoxyphenyl)amino]-2,3-dihydro-1H-inden-1-yl]methyl}amino)pyridine-4- carboxylic acid

3-({[(1R)-5-[(4-cyclopropoxyphenyl)(methyl)amino]-2,3-dihydro-1H-inden-1-yl]methyl}amino)pyridine-4- carboxylic acid

3-({[(1R)-5-{[4- (cyclopropylmethyl)phenyl](methyl)amino}-2,3-dihydro-1H-inden-1-yl]methyl}amino)pyridine-4- carboxylic acid

3-({[(1R)-5-[(4- cyclopropanecarbonylphenyl)(methyl)amino]-2,3-dihydro-1H-inden-1-yl]methyl}amino)pyridine-4- carboxylic acid

3-({[(3R)-6-{methyl[4-(propan-2-yl)phenyl]amino}-2,3-dihydro-1-benzofuran-3- yl]methyl}amino)pyridine-4-carboxylic acid

3-({[(3R)-6-{methyl[4-(propan-2-yloxy)phenyl]amino}-2,3-dihydro-1-benzofuran-3-yl]methyl}amino)pyridine-4-carboxylic acid

3-({[(3S)-6-(4-fluorophenyl)-2,3-dihydro-1-benzofuran-3-yl]methyl}amino)pyridine-4-carboxylic acid

3-({[(3S)-6-(4-cyanophenyl)-2,3-dihydro-1-benzofuran-3-yl]methyl}amino)pyridine-4-carboxylic acid

3-({[(3S)-6-(thiophen-3-yl)-2,3-dihydro-1-benzofuran-3-yl]methyl}amino)pyridine-4-carboxylic acid

3-({[(3S)-6-(5-methylthiophen-3-yl)-2,3-dihydro-1-benzofuran-3-yl]methyl}amino)pyridine-4-carboxylic acid

3-({[(3S)-6-(thiophen-2-yl)-2,3-dihydro-1-benzofuran-3-yl]methyl}amino)pyridine-4-carboxylic acid

3-({[(3S)-6-(5-methylthiophen-2-yl)-2,3-dihydro-1-benzofuran-3-yl]methyl}amino)pyridine-4-carboxylic acid

3-({[(3S)-6-[1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl]-2,3-dihydro-1-benzofuran-3- yl]methyl}amino)pyridine-4-carboxylic acidPreparation of the Substituted Pyridine Derivative Compounds

The compounds used in the reactions described herein are made accordingto organic synthesis techniques known to those skilled in this art,starting from commercially available chemicals and/or from compoundsdescribed in the chemical literature. “Commercially available chemicals”are obtained from standard commercial sources including Acros Organics(Pittsburgh, Pa.), Aldrich Chemical (Milwaukee, Wis., including SigmaChemical and Fluka), Apin Chemicals Ltd. (Milton Park, UK), AvocadoResearch (Lancashire, U.K.), BDH Inc. (Toronto, Canada), Bionet(Cornwall, U.K.), Chemservice Inc. (West Chester, Pa.), CrescentChemical Co. (Hauppauge, N.Y.), Eastman Organic Chemicals, Eastman KodakCompany (Rochester, N.Y.), Fisher Scientific Co. (Pittsburgh, Pa.),Fisons Chemicals (Leicestershire, UK), Frontier Scientific (Logan,Utah), ICN Biomedicals, Inc. (Costa Mesa, Calif.), Key Organics(Cornwall, U.K.), Lancaster Synthesis (Windham, N.H.), MaybridgeChemical Co. Ltd. (Cornwall, U.K.), Parish Chemical Co. (Orem, Utah),Pfaltz & Bauer, Inc. (Waterbury, Conn.), Polyorganix (Houston, Tex.),Pierce Chemical Co. (Rockford, Ill.), Riedel de Haen AG (Hanover,Germany), Spectrum Quality Product, Inc. (New Brunswick, N.J.), TCIAmerica (Portland, Oreg.), Trans World Chemicals, Inc. (Rockville, Md.),and Wako Chemicals USA, Inc. (Richmond, Va.).

Methods known to one of ordinary skill in the art are identified throughvarious reference books and databases. Suitable reference books andtreatise that detail the synthesis of reactants useful in thepreparation of compounds described herein, or provide references toarticles that describe the preparation, include for example, “SyntheticOrganic Chemistry”, John Wiley & Sons, Inc., New York; S. R. Sandler etal., “Organic Functional Group Preparations,” 2nd Ed., Academic Press,New York, 1983; H. O. House, “Modern Synthetic Reactions”, 2nd Ed., W.A. Benjamin, Inc. Menlo Park, Calif. 1972; T. L. Gilchrist,“Heterocyclic Chemistry”, 2nd Ed., John Wiley & Sons, New York, 1992; J.March, “Advanced Organic Chemistry: Reactions, Mechanisms andStructure”, 4th Ed., Wiley-Interscience, New York, 1992. Additionalsuitable reference books and treatise that detail the synthesis ofreactants useful in the preparation of compounds described herein, orprovide references to articles that describe the preparation, includefor example, Fuhrhop, J. and Penzlin G. “Organic Synthesis: Concepts,Methods, Starting Materials”, Second, Revised and Enlarged Edition(1994) John Wiley & Sons ISBN: 3-527-29074-5; Hoffman, R. V. “OrganicChemistry, An Intermediate Text” (1996) Oxford University Press, ISBN0-19-509618-5; Larock, R. C. “Comprehensive Organic Transformations: AGuide to Functional Group Preparations” 2nd Edition (1999) Wiley-VCH,ISBN: 0-471-19031-4; March, J. “Advanced Organic Chemistry: Reactions,Mechanisms, and Structure” 4th Edition (1992) John Wiley & Sons, ISBN:0-471-60180-2; Otera, J. (editor) “Modern Carbonyl Chemistry” (2000)Wiley-VCH, ISBN: 3-527-29871-1; Patai, S. “Patai's 1992 Guide to theChemistry of Functional Groups” (1992) Interscience ISBN: 0-471-93022-9;Solomons, T. W. G. “Organic Chemistry” 7th Edition (2000) John Wiley &Sons, ISBN: 0-471-19095-0; Stowell, J. C., “Intermediate OrganicChemistry” 2nd Edition (1993) Wiley-Interscience, ISBN: 0-471-57456-2;“Industrial Organic Chemicals: Starting Materials and Intermediates: AnUllmann's Encyclopedia” (1999) John Wiley & Sons, ISBN: 3-527-29645-X,in 8 volumes; “Organic Reactions” (1942-2000) John Wiley & Sons, in over55 volumes; and “Chemistry of Functional Groups” John Wiley & Sons, in73 volumes.

Specific and analogous reactants may also be identified through theindices of known chemicals prepared by the Chemical Abstract Service ofthe American Chemical Society, which are available in most public anduniversity libraries, as well as through on-line databases (the AmericanChemical Society, Washington, D.C., may be contacted for more details).Chemicals that are known but not commercially available in catalogs maybe prepared by custom chemical synthesis houses, where many of thestandard chemical supply houses (e.g., those listed above) providecustom synthesis services. A reference for the preparation and selectionof pharmaceutical salts of the substituted pyridine and pyridazinederivative compounds described herein is P. H. Stahl & C. G. Wermuth“Handbook of Pharmaceutical Salts”, Verlag Helvetica Chimica Acta,Zurich, 2002.

The substituted pyridine derivative compounds are prepared by thegeneral synthetic routes described below in Schemes 1-3.

Referring to Scheme 1, compound A and an amine compound B are mixed andtreated under a variety of conditions to form compound C. For example,the mixture of compound A and an amine B can be subjected to microwaveirradiation in an appropriate solvent, at temperatures ranging from 120°C. to 172° C. The ester compound E can be prepared from compound C andan alcohol D using a coupling reagent, such as HATU, in the presence ofa base.

Referring to Scheme 2, compound F and an aldehyde compound G are mixedand treated under reductive amination conditions to form compound C. Theester compound E can be prepared from compound C and an alcohol D usinga coupling reagent, such as HATU, in the presence of a base.

Referring to Scheme 3, compound H and an amine compound B are mixed andtreated under a variety of conditions to form compound E. For example,the mixture of compound H and an amine B can be subjected to a Buchwaldreaction under microwave irradiation in an appropriate solvent, attemperatures ranging from 100° C. to 120° C. The ester compound E can behydrolyzed to give compound C, using basic conditions such as 1N aq.NaOH.

Pharmaceutical Compositions

In certain embodiments, the substituted pyridine derivative compound asdescribed herein is administered as a pure chemical. In otherembodiments, the substituted pyridine derivative compound as describedherein is combined with a pharmaceutically suitable or acceptablecarrier (also referred to herein as a pharmaceutically suitable (oracceptable) excipient, physiologically suitable (or acceptable)excipient, or physiologically suitable (or acceptable) carrier) selectedon the basis of a chosen route of administration and standardpharmaceutical practice as described, for example, in Remington: TheScience and Practice of Pharmacy (Gennaro, 21st Ed. Mack Pub. Co.,Easton, Pa. (2005)), the disclosure of which is hereby incorporatedherein by reference, in its entirety.

Accordingly, provided herein is a pharmaceutical composition comprisingat least one substituted pyridine derivative compound, or astereoisomer, prodrug, pharmaceutically acceptable salt, hydrate,solvate, or N-oxide thereof, together with one or more pharmaceuticallyacceptable carriers and, optionally, other therapeutic and/orprophylactic ingredients. The carrier(s) (or excipient(s)) is acceptableor suitable if the carrier is compatible with the other ingredients ofthe composition and not deleterious to the recipient (i.e., the subject)of the composition.

One embodiment provides a pharmaceutical composition comprising apharmaceutically acceptable carrier and a compound of Formulas (I),(II), (IIa) (III), (IV) or (V) or a tautomer, stereoisomer, geometricisomer, N-oxide, or pharmaceutically acceptable salt thereof.

In certain embodiments, the substituted pyridine derivative compound asdescribed by Formulas (I), (II), (IIa) (III), (IV) or (V) issubstantially pure, in that it contains less than about 5%, or less thanabout 1%, or less than about 0.1%, of other organic small molecules,such as contaminating intermediates or by-products that are created, forexample, in one or more of the steps of a synthesis method.

Suitable oral dosage forms include, for example, tablets, pills,sachets, or capsules of hard or soft gelatin, methylcellulose or ofanother suitable material easily dissolved in the digestive tract.Suitable nontoxic solid carriers can be used which include, for example,pharmaceutical grades of mannitol, lactose, starch, magnesium stearate,sodium saccharin, talcum, cellulose, glucose, sucrose, magnesiumcarbonate, and the like. (See, e.g., Remington: The Science and Practiceof Pharmacy (Gennaro, 21^(st) Ed. Mack Pub. Co., Easton, Pa. (2005)).

The dose of the composition comprising at least one substituted pyridinederivative compound as described herein may differ, depending upon thepatient's (e.g., human) condition, that is, stage of the disease,general health status, age, and other factors that a person skilled inthe medical art will use to determine dose.

Pharmaceutical compositions may be administered in a manner appropriateto the disease to be treated (or prevented) as determined by personsskilled in the medical arts. An appropriate dose and a suitable durationand frequency of administration will be determined by such factors asthe condition of the patient, the type and severity of the patient'sdisease, the particular form of the active ingredient, and the method ofadministration. In general, an appropriate dose and treatment regimenprovides the composition(s) in an amount sufficient to providetherapeutic and/or prophylactic benefit (e.g., an improved clinicaloutcome, such as more frequent complete or partial remissions, or longerdisease-free and/or overall survival, or a lessening of symptomseverity. Optimal doses may generally be determined using experimentalmodels and/or clinical trials. The optimal dose may depend upon the bodymass, weight, or blood volume of the patient.

For the substituted pyridine derivative compounds described herein oraldoses typically range from about 1.0 mg to about 1000 mg, one to fourtimes, or more, per day.

Histone Demethylase

Chromatin is the complex of DNA and protein that makes up chromosomes.Histones are the major protein component of chromatin, acting as spoolsaround which DNA winds. Changes in chromatin structure are affected bycovalent modifications of histone proteins and by non-histone bindingproteins. Several classes of enzymes are known which can covalentlymodify histones at various sites.

Proteins can be post-translationally modified by methylation on aminogroups of lysines and guanidino groups of arginines or carboxymethylatedon aspartate, glutamate, or on the C-terminus of the protein.Post-translational protein methylation has been implicated in a varietyof cellular processes such as RNA processing, receptor mediatedsignaling, and cellular differentiation. Post-translational proteinmethylation is widely known to occur on histones, such reactions knownto be catalyzed by histone methyltransferases, which transfer methylgroups from S-adenyosyl methionine (SAM) to histones. Histonemethylation is known to participate in a diverse range of biologicalprocesses including heterochromatin formation, X-chromosomeinactivation, and transcriptional regulation (Lachner et al., (2003) J.Cell Sci. 116:2117-2124; Margueron et al., (2005) Curr. Opin. Genet.Dev. 15:163-176).

Unlike acetylation, which generally correlates with transcriptionalactivation, whether histone methylation leads to transcriptionactivation or repression depends on the particular site of methylationand the degree of methylation (e.g., whether a particular histone lysineresidue is mono-, di-, or tri-methylated). However, generally,methylation on H3K9, H3K27 and H4K20 is linked to gene silencing, whilemethylation on H3K4, H3K36, and H3K79 is generally associated withactive gene expression. In addition, tri- and di-methylation of H3K4generally marks the transcriptional start sites of actively transcribedgenes, whereas mono-methylation of H3K4 is associated with enhancersequences.

A “demethylase” or “protein demethylase,” as referred to herein, refersto an enzyme that removes at least one methyl group from an amino acidside chain. Some demethylases act on histones, e.g., act as a histone H3or H4 demethylase. For example, an H3 demethylase may demethylate one ormore of H3K4, H3K9, H3K27, H3K36 and/or H3K79. Alternately, an H4demethylase may demethylate histone H4K20. Demethylases are known whichcan demethylate either a mono-, di- and/or a tri-methylated substrate.Further, histone demethylases can act on a methylated core histonesubstrate, a mononucleosome substrate, a dinucleosome substrate and/oran oligonucleosome substrate, peptide substrate and/or chromatin (e.g.,in a cell-based assay).

The first lysine demethylase discovered was lysine specific demethylase1 (LSD1/KDM1), which demethylates both mono- and di-methylated H3K4 orH3K9, using flavin as a cofactor. A second class of Jumonji C (JmjC)domain containing histone demthylases were predicted, and confirmed whena H3K36 demethylase was found using a formaldehyde release assay, whichwas named JmjC domain containing histone demethylase 1 (JHDM1/KDM2A).

More JmjC domain-containing proteins were subsequently identified andthey can be phylogenetically clustered into seven subfamilies: JHDM1,JHDM2, JHDM3, JMJD2, JARID, PHF2/PHF8, UTX/UTY, and JmjC domain only.

JMJD2 Family

The JMJD2 family of proteins are a family of histone-demethylases knownto demethylate tri- and di-methylated H3-K9, and were the firstidentified histone tri-methyl demethylases. In particular, ectopicexpression of JMJD2 family members was found to dramatically decreaselevels of tri- and di-methylated H3-K9, while increasing levels ofmono-methylated H3-K9, which delocalized Heterochromatin Protein 1 (HP1)and reduced overall levels of heterochromatin in vivo. Members of theJMJD2 subfamily of jumonji proteins include JMJD2C and its homologuesJMJD2A, JMJD2B, JMJD2D and JMJD2E. Common structural features found inthe JMJD2 subfamily of Jumonji proteins include the JmjN, JmjC, PHD andTdr sequences.

JMJD2C, also known as GASC1 and KDM4C, is known to demethylatetri-methylated H3K9 and H3K36. Histone demethylation by JMJD2C occursvia a hydroxylation reaction dependent on iron and α-ketoglutarate,wherein oxidative decarboxylation of α-ketoglutarate by JMJD2C producescarbon dioxide, succinate, and ferryl and ferryl subsequentlyhydroxylates a methyl group of lysine H3K9, releasing formaldehyde.JMJD2C is known to modulate regulation of adipogenesis by the nuclearreceptor PPARγ and is known to be involved in regulation of self-renewalin embryonic stem cells.

JARID Family

As used herein, a “JARID protein” includes proteins in the JARIDsubfamily (e.g., JARID1A, JARID1B, JARID1C and JARID1D proteins) and theJARID2 subfamily, as well as homologues thereof. A further descriptionand listing of JARID proteins can be found in Klose et al. (2006) NatureReviews/Genetics 7:715-727. The JARID1 family contains several conserveddomains: JmjN, ARID, JmjC, PHD and a C5HC2 zing finger.

JARID1A, also called KDM5A or RBP2, was initially found as a bindingpartner of retinoblastoma (Rb) protein. JARID1A was subsequently foundto function as a demethylase of tri- and di-methylated H3K4, and hasbeen found to promote cell growth, while inhibiting senescence anddifferentiation. For instance, abrogation of JARID1A from mouse cellsinhibits cell growth, induces senescence and differentiation, and causesloss of pluripotency of embryonic stem cells in vitro. JARID1A has beenfound to be overexpressed in gastric cancer and the loss of JARID1A hasbeen found to reduce tumorigenesis in a mouse cancer model.Additionally, studies have demonstrated that loss of the retinoblastomebinding protein 2 (RBP2) histone demethylase suppresses tumorigenesis inmice lacking Rb1 or Men1 (Lin et al. Proc. Natl. Acad. Sci. USA, Aug.16, 2011, 108(33), 13379-86; doi: 10.1073/pnas.1110104108) and theauthors of the study concluded that RBP2-inhibitory drugs would haveanti-cancer activity.

JARID1B, also referred to as KDM5B and PLU1, was originally found inexperiments to discover genes regulated by the HER2 tyrosine kinase.JARID1B has consistently been found to be expressed in breast cancercell lines, although restriction of JARID1B has been found in normaladult tissues, with the exception of the testis. In addition, 90% ofinvasive ductal carcinomas have been found to express JARID1B. Inaddition, JARID1B has been found to be up-regulated in prostate cancers,while having more limited expression in benign prostate, and has alsobeen found to be up-regulated in bladder cancer and lung cancer (bothSCLC and NSCLC). JARID1B has also been found to repress tumor suppressorgenes such as BRCA1, CAV1 and 14-3-3σ, and knockdown of JARID1B wasfound to increase the levels of tri-methylated H3K4 at these genes.

UTX/UTY Family

UTX/UTY family includes KDM6A, KDM6B, and UTY. KDM6A, also referred toas UTX, and KDM6B, also referred to as JMJD3, act on di- andtrimethylated H3K27 and are important for development whereas thesubstrate and role of UTY remains to be elucidated. Both KDM6A (UTX) andKDM6B (JMJD3) have demonstrated tumor-suppressive characteristics byfunctioning as antagonists to the oncogenic polycomb (PcG) proteins. PcGproteins are important repressive histone marks that catalyze the tri-and dimethylation of H3K27 The PcG genes have been characterized asoncogenes that are frequently overexpressed or amplified in cancer.

In an additional embodiment is the method for inhibiting ahistone-demethylase enzyme comprising contacting the enzyme with asubstituted pyridine derivative compound as disclosed herein, whereinthe histone-demethylase enzyme comprises a JmjC domain. In an additionalembodiment is the method for inhibiting a histone-demethylase enzymecomprising contacting the enzyme with a substituted pyridine derivativecompound as disclosed herein, wherein the histone-demethylase enzyme isselected from JARID1A, JARID1B, or JMJD2C. In an additional embodimentis the method for inhibiting a histone-demethylase enzyme comprisingcontacting the enzyme with a substituted pyridine derivative compound asdisclosed herein, wherein the histone-demethylase enzyme is selectedfrom JARID1A, JARID1B, JMJD2C, and JMJD3. In one embodiment is themethod for inhibiting the histone-demethylase enzyme JMJD3 comprisingcontacting the JMJD3 enzyme with a substituted pyridine derivativecompound as disclosed herein. In one embodiment is the method forinhibiting the histone-demethylase enzyme JMJD2C comprising contactingthe JMJD2C enzyme with a substituted pyridine derivative compound asdisclosed herein.

Methods of Treatment

Disclosed herein are methods of modulating demethylation in a cell or ina subject, either generally or with respect to one or more specifictarget genes. Demethylation can be modulated to control a variety ofcellular functions, including without limitation: differentiation;proliferation; apoptosis; tumorigenesis, leukemogenesis or otheroncogenic transformation events; hair loss; or sexual differentiation.For example, in particular embodiments, provided herein is a method oftreating a disease regulated by histone methylation and/or demethylationin a subject in need thereof by modulating the activity of a demethylasecomprising a JmjC domain (e.g., a histone demethylase such as a JHDMprotein(s)).

In one embodiment is provided a method of treating cancer in a patientin need thereof comprising administering to the patient a compositioncomprising a compound of Formula (I), (II), (IIa) (III), (IV) or (V) ora pharmaceutically acceptable salt thereof. In a further embodiment isthe method for treating cancer in a patient wherein the cancer isselected from prostate cancer, breast cancer, bladder cancer, lungcancer or melanoma.

In an additional embodiment is a method for inhibiting the growth of atumor comprising exposing the tumor to a composition comprising acompound of Formula (I), (II), (IIa) (III), (IV) or (V) or apharmaceutically acceptable salt thereof, wherein the tumor ischaracterized by a loss of retinoblastoma gene (RB1) function.

In an additional embodiment is a method for inhibiting the growth of atumor comprising exposing the tumor to a composition comprising acompound of Formula (I), (II), (IIa) (III), (IV) or (V) or apharmaceutically acceptable salt thereof, wherein the tumor ischaracterized by a loss of multiple endocrine neoplasia type 1 gene(Men1) function.

Other embodiments and uses will be apparent to one skilled in the art inlight of the present disclosures. The following examples are providedmerely as illustrative of various embodiments and shall not be construedto limit the invention in any way.

EXAMPLES

I. Chemical Synthesis

Unless otherwise noted, reagents and solvents were used as received fromcommercial suppliers. Anhydrous solvents and oven-dried glassware wereused for synthetic transformations sensitive to moisture and/or oxygen.Yields were not optimized. Reaction times are approximate and were notoptimized. Column chromatography and thin layer chromatography (TLC)were performed on silica gel unless otherwise noted. Spectra are givenin ppm (δ) and coupling constants, J are reported in Hertz. For protonspectra the solvent peak was used as the reference peak.

Preparation 1a: 6-bromo-1,2,3,4-tetrahydronaphthalen-1-one

A solution of NaNO₂ (2.35 g, 34 mmol) in water (10 mL) was addeddropwise to the solution of 6-amino-1,2,3,4-tetrahydronaphthalen-1-one(5.0 g, 31 mmol) in 25% HBr (16 mL) at 0° C. The suspension was thentransferred to a stirred mixture of CuBr (8.9 g, 62 mmol) in 48% HBr (30mL) at 0° C. The resulting mixture was allowed to warm to rt and stirredfor 1 h. The mixture was extracted with EtOAc, dried (Na₂SO₄), andconcentrated. The residue was purified by silica gel chromatography(0%-60% EtOAc/Hex) to give 5.6 g (80%) of the title compound as a lightyellow oil. ¹H NMR (400 MHz, CDCl₃): δ 2.10-2.16 (2H, m), 2.64 (2H, t,J=6.4 Hz), 2.94 (2H, t, J=6.0 Hz), 7.42 (1H, s), 7.44 (1H, s), 7.87 (1H,d, J=8.9 Hz). [M+H] calc'd for C₁₀H₉BrO, 225, 227; found 225, 227.

Preparation 1b:6-[methyl(phenyl)amino]-1,2,3,4-tetrahydronaphthalen-1-one

To a solution of 6-bromo-1,2,3,4-tetrahydronaphthalen-1-one (2.0 g, 8.9mmol) in toluene (20 mL) was added N-methylaniline (960 mg, 8.9 mmol),Cs₂CO₃ (4.4 g, 13.4 mmol), BINAP (310 mg, 0.5 mmol) and Pd(OAc)₂ (110mg, 0.5 mmol). The mixture was stirred overnight at 100° C. undernitrogen. The mixture was filtered and concentrated, and the residue waspurified by silica gel chromatography (30%-80% EtOAc/Hex) to give 1.52 g(68%) of the title compound as a light brown oil. [M+H] calc'd forC₁₇H₁₇NO, 252; found 252.

Preparation 1c:5-(aminomethyl)-N-methyl-N-phenyl-7,8-dihydronaphthalen-2-amine,Hydrochloride

To a solution of Preparation 1b (1.52 g, 6.0 mmol) and ZnI₂ (150 mg) intoluene (20 mL) was added TMSCN (1.2 g, 12 mmol) at rt. The mixture washeated at 60° C. for 2 h. The reaction mixture was cooled to rt anddiluted with addition of THF (20 mL). A solution of LAH (5 mL, 2.4 M inTHF, 12 mmol) was added slowly at rt, and the solution stirred for 0.5h. The reaction was quenched with the addition of EtOAc (10 mL), andthen water (1 mL) and aqueous 1 M NaOH (1 mL). The solution was dried(Na₂SO₄) and concentrated to give 1.52 g (89%) of the crude1-(aminomethyl)-6-[methyl(phenyl)amino]-1,2,3,4-tetrahydronaphthalen-1-olas a white solid.

Into a solution of this intermediate (1.52 g, 5.4 mmol) in methanol (20mL) was bubbled dry HCl gas for 2 min, while the reaction was cooled soas to not allow the temperature to exceed 30° C. The mixture was thenstirred at rt for 1 h. The methanol was evaporated under reducedpressure to give 1.4 g (98%) of the title compound as the HCl salt.[M+H] calc'd for C₁₈H₂₀N₂, 265; found 265.

Preparation 1d:5-(aminomethyl)-N-methyl-N-phenyl-5,6,7,8-tetrahydronaphthalen-2-amine

To a solution of Preparation 1c (1.4 g, 5.3 mmol) in MeOH (30 mL) andconc. HCl (three drops) was added 10% Pd/C (200 mg) at rt under N₂. Thesuspension was stirred at rt for 16 h under hydrogen at 50 psi. Thereaction mixture was filtered through Celite, adjusted to pH=8˜9 withsat. Na₂CO₃, dried (Na₂SO₄), and concentrated to give 830 mg (59%) ofthe title compound as a yellow oil. [M+H] calc'd for C₁₈H₂₂N₂, 267;found 267.

Preparation 1e: Methyl3-[({6-[methyl(phenyl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl}methyl)amino]pyridine-4-carboxylate

To a solution of Preparation 1d (500 mg, 1.88 mmol) in DMA (12 mL) wasadded methyl 3-fluoroisonicotinate (300 mg, 1.93 mmol). The reactionmixture was stirred at 170° C. for 1 h in a microwave. The reactionmixture was poured into water and extracted with EtOAc. Organics werewashed with brine, dried (Na₂SO₄), and concentrated. The residue waspurified by silica gel chromatography (20-80% EtOAc/Hex) to give 200 mg(26%) of the title compound as a yellow oil. [M+H] calc'd forC₂₅H₂₇N₃O₂, 402; found 402.

Preparation 1f: methyl3-({[(1S)-6-[methyl(phenyl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate,and Preparation 2f: methyl3-({[(1R)-6-[methyl(phenyl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

Preparation 1e (200 mg) was separated by chiral HPLC (Column: ChiralcelIA, 250 mm*4.6 mm 5 um; Mobile phase: Hex:EtOH=85:15; F: 1.0 mL/min; W:230 nm; T=30° C.) to give 95 mg (47%) of Preparation if (6.54 min) and92 mg (46%) of Preparation 2f (7.91 min), each as a yellow oil.

Example 1:3-({[(1S)-6-[methyl(phenyl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylicAcid

To a solution of Preparation if (95 mg, 0.24 mmol) in THF (6 mL) and H₂O(2 mL) was added LiOH.H₂O (31 mg, 0.72 mmol) at rt, and the reactionmixture was stirred overnight. The reaction mixture was concentrated toremove THF, and the residue was diluted with water and acidified topH=3˜4 with 1.0 N aqueous HCl solution. The precipitate was collected byfiltration and washed with EtOAc/ether. The solid was dried under vacuumto give 52 mg (56%) of the title compound as a yellow solid. ¹H NMR (400MHz, DMSO-d₆): δ 1.64-1.67 (1H, m), 1.77-1.84 (3H, m), 2.65-2.68 (2H, d,J=5.6 Hz), 3.04-3.07 (1H, m), 3.21 (3H, s), 3.41-3.47 (1H, m), 3.56-3.60(1H, m), 6.78-6.92 (5H, m), 7.21-7.25 (3H, m), 7.55 (1H, d, J=5.2 Hz),7.82 (1H, d, J=5.2 Hz), 8.36 (1H, s). [M+H] Calc'd for C₂₄H₂₅N₃O₂, 388;Found, 388.

Example 2:3-({[(1R)-6-[methyl(phenyl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 53% yield from Preparation 2faccording to the procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ1.64-1.68 (1H, m), 1.77-1.84 (3H, m), 2.65-2.68 (2H, d, J=5.6 Hz),3.04-3.07 (1H, m), 3.21 (3H, s), 3.41-3.47 (1H, m), 3.56-3.60 (1H, m),6.78-6.92 (5H, m), 7.21-7.25 (3H, m), 7.56 (1H, d, J=4.8 Hz), 7.82 (1H,d, J=5.2 Hz), 8.36 (1H, s). [M+H] calc'd for C₂₄H₂₅N₃O₂, 388; found 388.

Preparation 3a: (6-bromo-3,4-dihydronaphthalen-1-yl)methanamine,Hydrochloride

To a solution of 6-bromo-1,2,3,4-tetrahydronaphthalen-1-one (5.00 g,22.0 mmol) and ZnI₂ (300 mg) in toluene (50 mL) was added TMSCN (4.36 g,44.0 mmol) at rt. The mixture was heated at 60° C. overnight. Thereaction mixture was cooled to rt, and a solution of LAH (20.0 mL, 2.4 Min THF, 44.0 mmol) was added slowly. The reaction stirred at 40° C. for2 h. The reaction was cooled to 0° C. was quenched with addition ofEtOAc (10 mL) at 0° C., and then water (5 mL) and aqueous 10% NaOH (5mL). The mixture was filtered through Celite and concentrated to givethe 4.5 g (79%) of the crude1-(aminomethyl)-6-bromo-1,2,3,4-tetrahydronaphthalen-1-ol intermediateas a brown oil. To a solution of this intermediate (4.5 g, 17.4 mmol) intoluene (100 mL) was added 4N HCl/dioxane (20 mL) solution, and themixture was stirred at reflux for 10 min. The mixture was cooled to roomtemperature and concentrated to give 3.6 g (75%) of the title compoundas a tan solid. [M+H] calc'd for C₁₁H₁₂BrN, 237, 239; found 237, 239.

Preparation 3b: tert-butylN-[(6-bromo-3,4-dihydronaphthalen-1-yl)methyl]carbamate

To a solution of Preparation 3a (1.05 g, 3.84 mmol) in DCM (10 mL) wasadded TEA (1.6 mL, 11.5 mmol), Boc₂O (2.1 g, 9.6 mmol) and DMAP (94 mg,0.77 mmol). The mixture was stirred at rt for 1 h. The reaction wasconcentrated, and the residue was purified by silica gel chromatography(20-60% EtOAc/Hex) to give 900 mg (69%) of the title compound as a whitesolid. ¹H NMR (400 MHz, CDCl₃): δ 1.44 (9H, s), 2.24-2.29 (2H, m),2.70-2.74 (2H, m), 4.12 (2H, d, J=4.8 Hz), 4.56 (1H, br s), 6.03 (1H, t,J=4.4 Hz), 7.10 (1H, d, J=8.0 Hz), 7.26-7.32 (2H, m).

Preparation 3c: Tert-ButylN-{[6-(2-oxopyrrolidin-1-yl)-3,4-dihydronaphthalen-1-yl]methyl}carbamate

To a solution of Preparation 3b (900 mg, 2.67 mmol) in dioxane (10 mL)was added 2-pyrrolidinone (680 mg, 8.0 mmol), Cs₂CO₃ (1.3 g, 4.0 mmol),BINAP (283 mg, 0.45 mmol) and Pd(OAc)₂ (60 mg, 0.27 mmol). The mixturewas stirred at 100° C. for 4 h under nitrogen. The mixture was filteredand concentrated, and the residue was purified by silica gelchromatography (30-80% EtOAc/Hex) to give 470 mg (51%) of the titlecompound as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ 1.38 (9H, s),2.01-2.08 (2H, m), 2.18-2.23 (2H, m), 2.45-2.50 (2H, m), 2.68 (2H, t,J=8.0 Hz), 3.81 (2H, t, J=7.0 Hz), 3.92 (2H, d, J=4.8 Hz), 5.86 (1H, s),7.02 (1H, t, J=5.4 Hz), 7.22 (1H, d, J=8.8 Hz), 7.42 (1H, d, J=8.4 Hz),7.48 (1H, s).

Preparation 3d:1-[5-(aminomethyl)-7,8-dihydronaphthalen-2-yl]pyrrolidin-2-one,Hydrochloride

A solution of Preparation 3c (470 mg, 1.37 mmol) in 4 N HCl/dioxane (10mL) was stirred overnight at rt. The mixture was concentrated to 330 mg(99%) of the title compound as a tan oil. ¹H NMR (400 MHz, MeOD-d₄): δ2.19-2.23 (2H, m), 2.38-2.41 (2H, m), 2.63 (2H, t, J=8.2 Hz), 2.84 (2H,t, J=8.2 Hz), 3.96 (2H, t, J=7.0 Hz), 4.02 (2H, s), 6.26 (1H, t, J=4.4Hz), 7.31 (1H, d, J=8.8 Hz), 7.52 (1H, s), 7.54 (1H, d, J=6.8 Hz). [M+H]calc'd for C₁₅H₁₈N₂O, 243; found 243.

Preparation 3e:1-[5-(aminomethyl)-5,6,7,8-tetrahydronaphthalen-2-yl]pyrrolidin-2-one

To a solution of Preparation 3d (330 mg, 1.36 mmol) in MeOH (10 mL) andconc. HCl (one drop) was added 10% Pd/C (50 mg) at rt under N₂. Thesuspension was stirred overnight under hydrogen at 50 psi. The reactionmixture was filtered through Celite, adjusted to pH=8˜9 with sat.Na₂CO₃, dried (Na₂SO₄), and concentrated to give 240 mg (72%) of thetitle compound as a white solid. [M+H] calc'd for C₁₅H₂₀N₂O, 245; found245.

Preparation 3f: methyl3-({[6-(2-oxopyrrolidin-1-yl)-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 15% yield from Preparation 3eaccording to the general procedure for Preparation 1e. [M+H] calc'd forC₂₂H₂₅N₃O₃, 380; found 380.

Example 3:3-({[6-(2-oxopyrrolidin-1-yl)-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 92% yield from Preparation 3faccording to the general procedure for Example 1. ¹H NMR (400 MHz,DMSO-d₆): δ 1.65-1.69 (1H, m), 1.78-1.84 (3H, m), 2.00-2.07 (2H, m),2.44-2.50 (2H, m), 2.70-2.73 (2H, m), 3.06-3.10 (1H, m), 3.38-3.45 (1H,m), 3.54-3.58 (1H, m), 3.79 (2H, t, J=7.0 Hz), 7.29 (1H, d, J=8.0 Hz),7.34 (1H, s), 7.41 (1H, d, J=8.0 Hz), 7.55 (1H, d, J=5.2 Hz), 7.81 (1H,d, J=5.2 Hz), 8.34 (1H, s). [M+H] calc'd for C₂₁H₂₃N₃O₃, 366; found 366.

Preparation 4a:6-(1,2,3,4-tetrahydroquinolin-1-yl)-1,2,3,4-tetrahydronaphthalen-1-one

To a solution of 5-oxo-5,6,7,8-tetrahydronaphthalen-2-yl4-methylbenzene-1-sulfonate (1.0 g, 3.4 mmol) in THF (20 mL) was added1,2,3,4-tetrahydroquinoline (0.55 g, 4.1 mmol), Pd(OAc)₂ (92 mg, 0.41mmol), BINAP (383 mg, 0.61 mmol) and Cs₂CO₃ (1.7 g, 5.1 mmol). Themixture was heated to reflux under nitrogen overnight. The mixture wasfiltered and concentrated, and the residue was purified by silica gelchromatography (10% EtOAc/hexanes) to give 0.72 g (76%) of the titlecompound as a brown oil. ¹H NMR (400 MHz, CDCl₃): δ 7.94 (d, J=8.4 Hz,1H), 7.18-7.04 (m, 4H), 6.97 (d, J=2.4 Hz, 1H), 6.90 (dt, J=7.6 Hz, 1.2Hz, 1H), 3.69 (t, J=6.0 Hz, 2H), 2.87 (t, J=6.0 Hz, 2H), 2.77 (t, J=6.4Hz, 2H), 2.61 (t, J=6.4 Hz, 2H), 2.14-2.08 (m, 2H), 2.05-1.98 (m, 2H).[M+H] calc'd for C₁₉H₁₉NO, 278; found 278.

Preparation 4b:[6-(1,2,3,4-tetrahydroquinolin-1-yl)-3,4-dihydronaphthalen-1-yl]methanamine,Hydrochloride

The title compound was prepared in 65% yield from Preparation 4aaccording to the general procedure for Preparation 3a. [M+H] calc'd forC₂₀H₂₂N₂, 291; found 291.

Preparation 4c:[6-(1,2,3,4-tetrahydroquinolin-1-yl)-1,2,3,4-tetrahydronaphthalen-1-yl]methanamine

The title compound was prepared in 96% yield from Preparation 4baccording to the general procedure for Preparation 3e, except that thereaction was heated at 50° C. [M+H] calc'd for C₂₀H₂₄N₂, 293; found 293.

Preparation 4d: methyl3-({[6-(1,2,3,4-tetrahydroquinolin-1-yl)-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

To a solution of Preparation 4c (0.49 g, 1.7 mmol) in toluene (10 mL)was added methyl 3-bromoisonicotinate (0.36 g, 1.7 mmol), Pd₂(dba)₃ (31mg, 0.033 mmol), Xantphos (58 mg, 0.1 mmol) and Cs₂CO₃ (0.76 g, 2.3mmol). The mixture was heated to reflux under nitrogen overnight. Themixture was filtered and concentrated, and the residue was purified bysilica gel chromatography (10-30% EtOAc/Hex) to give 0.35 g (49%) of thetitle compound as a pale yellow solid. ¹H NMR (400 MHz, CDCl₃): δ 8.34(s, 1H), 7.91 (d, J=5.2 Hz, 1H), 7.63 (d, J=5.2 Hz, 1H), 7.61-7.58 (m,1H), 7.21 (d, J=8.0 Hz, 1H), 7.05-6.99 (m, 2H), 6.93 (dd, J=8.0 Hz 7.6Hz, 1H), 6.75 (d, J=8.4 Hz, 1H), 6.68 (t, J=7.6 Hz, 1H), 3.90 (s, 3H),3.64-3.58 (m, 3H), 3.47-3.40 (m, 1H), 3.19-3.13 (m, 1H), 2.84 (t, J=6.4Hz, 2H), 2.78-2.74 (m, 2H), 2.06-2.00 (m, 2H), 1.97-1.75 (m, 4H). [M+H]calc'd for C₂₇H₂₉N₃O₂, 428; found 428.

Example 4:3-({[6-(1,2,3,4-tetrahydroquinolin-1-yl)-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 21% yield from Preparation 4daccording to the general procedure for Example 1. ¹H NMR (400 MHz,DMSO-d₆): δ 8.35 (s, 1H), 7.82 (d, J=4.4 Hz, 1H), 7.56 (d, J=4.4 Hz,1H), 7.31 (d, J=7.2 Hz, 1H), 7.01-6.93 (m, 3H), 6.86 (dd, J=7.6 Hz, 8.0Hz, 1H), 6.61 (dd, J=7.6 Hz, 7.2 Hz, 1H), 6.55 (d, J=8.0 Hz, 1H),3.62-3.51 (m, 3H), 3.47-3.40 (m, 1H), 3.11-3.06 (m, 1H), 2.78-2.66 (m,4H), 1.94-1.78 (m, 6H). [M+H] calc'd for C₂₆H₂₇N₃O₂, 414; found 414.

Preparation 5a:6-(2,3-dihydro-1H-indol-1-yl)-1,2,3,4-tetrahydronaphthalen-1-one

The title compound was prepared in 93% yield using indoline according tothe general procedure for Preparation 4a. [M+H] calc'd for C₁₈H₁₇NO,264; found 264.

Preparation 5b:[6-(2,3-dihydro-1H-indol-1-yl)-3,4-dihydronaphthalen-1-yl]methanamine,Hydrochloride

The title compound was prepared in 77% yield from Preparation 5aaccording to the general procedure for Preparation 3a. [M+H] calc'd forC₁₉H₂₀N₂, 277; found 277.

Preparation 5c:[6-(2,3-dihydro-1H-indol-1-yl)-1,2,3,4-tetrahydronaphthalen-1-yl]methanamine

The title compound was prepared in 97% yield from Preparation 5baccording to the general procedure for Preparation 3e, except thereaction was heated at 50° C. [M+H] calc'd for C₁₉H₂₂N₂, 279; found 279.

Preparation 5d: methyl3-({[6-(2,3-dihydro-1H-indol-1-yl)-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 24% yield from Preparation 5caccording to the general procedure for Preparation 1e. [M+H] calc'd forC₂₆H₂₇N₃O₂, 414; found 414.

Example 5:3-({[6-(2,3-dihydro-1H-indol-1-yl)-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 78% yield from Preparation 5daccording to the general procedure for Example 1. ¹H NMR (400 MHz,DMSO-d₆): δ 1.67-2.88 (4H, m), 2.71-2.77 (2H, m), 3.03-3.10 (3H, m),3.42-3.49 (1H, m), 3.56-3.58 (1H, m), 3.88 (2H, t, J=8.4 Hz), 6.67-6.71(1H, m), 6.93-6.94 (1H, m), 7.02-7.04 (3H, m), 7.15 (1H, d, J=7.2 Hz),7.29 (1H, d, J=8.4 Hz), 7.59 (1H, d, J=8.1 Hz), 8.84 (1H, d, J=4.8 Hz),8.39 (1H, s). [M+H] calc'd for C₂₅H₂₅N₃O₂, 400; found 400.

Preparation 6a: 6-bromo-3,4-dihydronaphthalene-1-carboxamide

To a solution of 6-bromo-1,2,3,4-tetrahydronaphthalen-1-one (5.46 g,24.3 mmol) and ZnI₂ (50 mg) in toluene (50 mL) was added TMSCN (4.82 mL,48.6 mmol), and the solution stirred at 60° C. overnight. The reactionwas cooled to rt, and H₂SO₄ (5.6 mL) was added. Then AcOH (34 mL), H₂SO₄(25 mL) and H₂O (4 mL) were added to the reaction, and it was heated to105° C. for 3 h. The mixture was cooled and poured over ice-water (250mL). The precipitate was collected by filtration, washed with water, anddried under vacuum to give 4.88 g (80%) of the title compound as anoff-white solid. ¹H NMR (400 MHz, DMSO-d₆): δ 2.25-2.33 (2H, m), 2.72(2H, t, J=8.0 Hz), 6.51 (1H, t, J=4.6 Hz), 7.20 (1H, br s), 7.35-7.40(3H, m), 7.65 (1H, br s). [M+H] calc'd for C₁₁H₁₀BrNO, 252, 254; found252, 254.

Preparation 6b: (1R)-6-bromo-1,2,3,4-tetrahydronaphthalene-1-carboxamide

To a solution of Preparation 6a (4.88 g, 19.4 mmol) in MeOH (75 mL) andTHF (75 mL) was added Ru(OAc)₂[s-binap] (82 mg, 0.097 mmol). The mixturewas heated at 40° C. under hydrogen at 120 psi overnight. The solutionwas concentrated to give the crude title compound (ee>80%).Re-crystallization from ACN gave 3.8 g (77%) of the title compound(ee>96%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ 1.55-1.62 (1H,m), 1.85-1.94 (3H, m), 2.67-2.74 (2H, m), 3.56 (1H, t, J=6.6 Hz), 6.98(1H, br s), 7.02 (1H, d, J=8.9 Hz), 7.25-7.29 (2H, m), 7.47 (1H, br s).[M+H] calc'd for C₁₁H₁₂BrNO, 254, 256; found 254, 256. AnalyticalColumn: Chiralcel: AS-H, Mobile phase: Hex:EtOH=60:40.

Preparation 6c:[(1R)-6-bromo-1,2,3,4-tetrahydronaphthalen-1-yl]methanamine

To a solution of Preparation 6b (2.5 g, 9.84 mmol) in THF (40 mL) wasadded BH₃.THF (39.4 mL, 1.0 M in THF, 39.4 mmol) at rt, and the solutionwas heated at 55° C. overnight. The solution was cooled and quenchedwith 10% H₂SO₄ (8 mL) and stirred for 6 h. The solution was made basicwith aq. NH₄OH and extracted (3×) with EtOAc. Organics were dried(Na₂SO₄) and concentrated to give 2.36 g (100%) of the crude titlecompound as a brown oil. [M+H] calc'd for C₁₁H₁₄BrN, 240, 242; found240, 242.

Preparation 6d: tert-butylN-{[(1R)-6-bromo-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}carbamate

To a solution of Preparation 6c (2.36 g, 9.83 mmol) and DIEA (2.23 mL,12.8 mmol) in DCM (50 mL) was added (Boc)₂O (2.58 g, 11.8 mmol), and thereaction stirred at rt for 2 h. The solution was washed with brine,dried (MgSO₄), and concentrated. Purification by silica gelchromatography (10-60% EtOAc/Hex) gave 3.02 g (90%) of the titlecompound as a white solid. ¹H NMR (400 MHz, CDCl₃): δ 1.45 (9H, s),1.72-1.85 (4H, m), 2.69-2.75 (2H, m), 2.88-2.96 (1H, m), 3.21-3.27 (1H,m), 3.35-3.42 (1H, m), 4.61 (1H, br s), 7.08 (1H, d, J=7.4 Hz),7.22-7.27 (2H, m). [M+H] calc'd for C₁₆H₂₂BrNO₂, 340, 342; found 340,342.

Preparation 6e: tert-butylN-{[(1R)-6-[(2-fluorophenyl)(methyl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}carbamate

To a suspension of Preparation 6d (150 mg, 0.442 mmol),2-fluoro-N-methylaniline (83 mg, 0.66 mmol), BINAP (14 mg, 0.022 mmol)and Cs₂CO₃ (216 mg, 0.664 mmol) in toluene (10 mL) was added Pd(OAc)₂ (3mg, 0.01 mmol) at rt under N₂. The reaction was stirred at 105° C.overnight. The mixture was filtered and concentrated. Purification bysilica gel chromatography (PE:EtOAc=8:1) gave 105 mg (62%) of the titlecompound as a brown oil. [M+H] calc'd for C₂₃H₂₉FN₂O₂, 385; found 385.

Preparation 6f:(5R)-5-(aminomethyl)-N-(2-fluorophenyl)-N-methyl-5,6,7,8-tetrahydronaphthalen-2-amine

To a solution of Preparation 6e (105 mg, 0.273 mmol) in EtOAc (5 mL) wasadded HCl/EtOAc (5 mL, 1.0 M), and the reaction was stirred at rt for 30min. The solution was concentrated, re-dissolved in EtOAc, and washedwith sat. Na₂CO₃. The organic layer was dried (Na₂SO₄) and concentratedto give 79 mg (100%) of the title compound as a yellow oil. [M+H] calc'dfor C₁₈H₂₁FN₂, 285; found 285.

Preparation 6g: Methyl3-({[(1R)-6-[(2-fluorophenyl)(methyl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 60% yield from Preparation 6faccording to the general procedure for Preparation 4d. [M+H] calc'd forC₂₅H₂₆FN₃O₂, 420; found 420.

Example 6:3-({[(1R)-6-[(2-fluorophenyl)(methyl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 79% yield from Preparation 6gaccording to the general procedure for Example 1. ¹H NMR (400 MHz,DMSO-d₆): δ 1.62-1.83 (4H, m), 2.61-2.63 (2H, m), 2.98-3.02 (1H, m),3.20 (3H, s), 3.34-3.41 (1H, m), 3.50-3.55 (1H, m), 6.44-6.48 (2H, m),7.13 (1H, d, J=8.4 Hz), 7.22-7.33 (4H, m), 7.56 (1H, d, J=5.2 Hz), 7.82(1H, d, J=4.8 Hz), 8.34 (1H, s). [M+H] calc'd for C₂₄H₂₄FN₃O₂, 406;found 406.

Preparation 7a: tert-butylN-{[(1R)-6-[(3-fluorophenyl)(methyl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}carbamate

The title compound was prepared in 56% yield from Preparation 6d and3-fluoro-N-methylaniline according to the general procedure forPreparation 6e. [M+H] calc'd for C₂₃H₂₉FN₂O₂, 385; found 385.

Preparation 7b:(5R)-5-(aminomethyl)-N-(3-fluorophenyl)-N-methyl-5,6,7,8-tetrahydronaphthalen-2-amine

The title compound was prepared in quantitative yield from Preparation7a according to the general procedure for Preparation 6f. [M+H] calc'dfor C₁₈H₂₁FN₂, 285; found 285.

Preparation 7c: Methyl3-({[(1R)-6-[(3-fluorophenyl)(methyl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 66% yield from Preparation 7baccording to the general procedure for Preparation 4d. [M+H] calc'd forC₂₅H₂₆FN₃O₂, 420; found 420.

Example 7:3-({[(1R)-6-[(3-fluorophenyl)(methyl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 76% yield from Preparation 7caccording to the general procedure for Example 1. ¹H NMR (400 MHz,DMSO-d₆): δ 1.67-1.86 (4H, m), 2.69-2.72 (2H, m), 3.09-3.12 (1H, m),3.31 (3H, s), 3.44-3.50 (1H, m), 3.59-3.64 (1H, m), 6.51-6.58 (3H, m),6.92-6.95 (2H, m), 7.14-7.20 (1H, m), 7.33 (1H, d, J=8.0 Hz), 7.58 (1H,d, J=5.2 Hz), 7.84 (1H, d, J=5.2 Hz), 8.38 (1H, s). [M+H] calc'd forC₂₄H₂₄FN₃O₂, 406; found 406.

Preparation 8a: tert-butylN-{[(1R)-6-[(4-fluorophenyl)(methyl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}carbamate

The title compound was prepared in 76% yield from Preparation 6d and4-fluoro-N-methylaniline according to the general procedure forPreparation 6e. [M+H] calc'd for C₂₃H₂₉FN₂O₂, 385; found 385.

Preparation 8b:(5R)-5-(aminomethyl)-N-(4-fluorophenyl)-N-methyl-5,6,7,8-tetrahydronaphthalen-2-amine

The title compound was prepared in quantitative yield from Preparation8a according to the general procedure for Preparation 6f. [M+H] calc'dfor C₁₈H₂₁FN₂, 285; found 285.

Preparation 8c: Methyl3-({[(1R)-6-[(4-fluorophenyl)(methyl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 42% yield from Preparation 8baccording to the general procedure for Preparation 4d. [M+H] calc'd forC₂₅H₂₆FN₃O₂, 420; found 420.

Example 8:3-({[(1R)-6-[(4-fluorophenyl)(methyl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 78% yield from Preparation 8caccording to the general procedure for Example 1. ¹H NMR (400 MHz,DMSO-d₆): δ 1.63-1.67 (1H, m), 1.75-1.85 (3H, m), 2.63-2.68 (2H, m),3.02-3.06 (1H, m), 3.19 (3H, s), 3.39-3.45 (1H, m), 3.53-3.59 (1H, m),6.68-6.73 (2H, m), 6.97-7.02 (2H, m), 7.07-7.13 (2H, m), 7.20 (1H, d,J=8.3 Hz), 7.56 (1H, d, J=5.0 Hz), 7.69 (1H, br s), 7.82 (1H, d, J=5.0Hz), 8.34 (1H, s), 13.36 (1H, br s). [M+H] calc'd for C₂₄H₂₄FN₃O₂, 406;found 406.

Preparation 9a: Tert-ButylN-{[(1R)-6-[(4-chlorophenyl)(methyl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}carbamate

To a solution of Preparation 6d (200 mg, 0.59 mmol) in toluene (5 mL)was added 4-chloro-N-methylaniline (100 mg, 0.7 mmol), Pd₂(dba)₃ (27 mg,0.03 mmol), Xantphos (51 mg, 0.15 mmol) and NaOtBu (68 mg, 0.7 mmol).The mixture was heated at 96° C. in a microwave for 1 h. The mixture wasfiltered and concentrated, and the residue was purified by silica gelchromatography (0-10% MeOH/DCM) to give 168 mg (76%) of the titlecompound as a pale yellow solid. [M+H] calc'd for C₂₃H₂₉ClN₂O₂, 401;found 401.

Preparation 9b:(5R)-5-(aminomethyl)-N-(4-chlorophenyl)-N-methyl-5,6,7,8-tetrahydronaphthalen-2-amine

Preparation 9a (168 mg, 0.42 mmol) was stirred in 50% TFA/DCM for 1 h.The solution was concentrated, and the residue was dissolved in EtOAcand washed with sat. NaHCO₃, dried (Na₂SO₄) and concentrated to give 126mg (quantitative) clear oil. [M+H] calc'd for C₁₈H₂₁ClN₂, 301; found301.

Preparation 9c: Methyl3-({[(1R)-6-[(4-chlorophenyl)(methyl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 12% yield from Preparation 9baccording to the general procedure for Preparation 4d. [M+H] calc'd forC₂₅H₂₆ClN₃O₂, 436; found 436.

Example 9:3-({[(1R)-6-[(4-chlorophenyl)(methyl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 76% yield from Preparation 9caccording to the general procedure for Example 1. ¹H NMR (400 MHz,MeOD): δ 1.73-1.79 (1H, m), 1.90-1.97 (3H, m), 2.73-2.81 (2H, m),3.12-3.15 (1H, s), 3.23 (3H, s), 3.42-3.48 (1H, m), 3.54-3.59 (1H, m),6.81-6.85 (4H, m), 7.15 (2H, dd, J=6.8, 2.2 Hz), 7.21 (1H, d, J=8.1 Hz),7.76-7.82 (2H, m), 8.21 (1H, s). [M+H] calc'd for C₂₄H₂₄ClN₃O₂, 422;found 422.

Preparation 10a: Tert-ButylN-{[(1R)-6-[ethyl(phenyl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}carbamate

The title compound was prepared in 59% yield from Preparation 6d andN-ethylaniline according to the general procedure for Preparation 9a.[M+H] calc'd for C₂₄H₃₂N₂O₂, 381; found 381.

Preparation 10b:(5R)-5-(aminomethyl)-N-ethyl-N-phenyl-5,6,7,8-tetrahydronaphthalen-2-amine

The title compound was prepared in quantitative yield from Preparation10a according to the general procedure for Preparation 9b. [M+H] calc'dfor C₁₉H₂₄N₂, 281; found 281.

Preparation 10c: methyl3-({[(1R)-6-[ethyl(phenyl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 82% yield from Preparation 10baccording to the general procedure for Preparation 4d. [M+H] calc'd forC₂₆H₂₉N₃O₂, 416; found 416.

Example 10:3-({[(1R)-6-[ethyl(phenyl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 90% yield from Preparation 10caccording to the general procedure for Example 1. ¹H NMR (400 MHz,DMSO-d₆): δ 1.11 (3H, t, J=7.0 Hz), 1.63-1.83 (4H, m), 2.62-2.70 (2H,m), 3.03-3.07 (1H, m), 3.39-3.46 (1H, m), 3.55-3.61 (1H, m), 3.70 (2H,q, J=7.0 Hz), 6.75-6.89 (5H, m), 7.19-7.25 (3H, m), 7.56 (1H, d, J=5.0Hz), 7.69 (1H, br s), 7.82 (1H, d, J=5.0 Hz), 8.34 (1H, s), 13.47 (1H,br s). [M+H] calc'd for C₂₅H₂₇N₃O₂, 402; found 402.

Preparation 11a: tert-butylN-{[(1R)-6-[methyl(pyridin-2-yl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}carbamate

The title compound was prepared in 41% yield from Preparation 6d andN-methyl-2-pyridinamine according to the general procedure forPreparation 6e. [M+H] calc'd for C₂₂H₂₉N₃O₂, 368; found 368.

Preparation 11b:N-[(5R)-5-(aminomethyl)-5,6,7,8-tetrahydronaphthalen-2-yl]-N-methylpyridin-2-amine

The title compound was prepared in 99% yield from Preparation 11aaccording to the general procedure for Preparation 6f. [M+H] calc'd forC₁₇H₂₁N₃, 268; found 268.

Preparation 11c: methyl3-({[(1R)-6-[methyl(pyridin-2-yl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 42% yield from Preparation 11baccording to the general procedure for Preparation 4d. [M+H] calc'd forC₂₄H₂₆N₄O₂, 403; found 403.

Example 11:3-({[(1R)-6-[methyl(pyridin-2-yl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 32% yield from Preparation 11caccording to the general procedure for Example 1. ¹H NMR (400 MHz,DMSO-d₆): δ 1.67-1.71 (1H, m), 1.80-1.88 (3H, m), 2.70-2.74 (2H, m),3.02-3.05 (1H, m), 3.23-3.29 (1H, m), 3.40 (3H, s), 3.47-3.50 (1H, m),6.48 (1H, d, J=8.8 Hz), 6.61-6.64 (1H, m), 7.00 (1H, s), 7.02 (1H, d,J=8.0 Hz), 7.37-7.41 (2H, m), 7.54 (1H, d, J=4.8 Hz), 7.68 (1H, d, J=4.8Hz), 8.05 (1H, s), 8.13 (1H, d, J=4.8 Hz), 9.19 (1H, br s). [M+H] calc'dfor C₂₃H₂₄N₄O₂, 389; found 389.

Preparation 12a: tert-butylN-{[(1R)-6-[methyl(pyridin-3-yl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}carbamate

The title compound was prepared in 77% yield from Preparation 6d andN-methyl-3-pyridinamine according to the general procedure forPreparation 9a. [M+H] calc'd for C₂₂H₂₉N₃O₂, 368; found 368.

Preparation 12b:N-[(5R)-5-(aminomethyl)-5,6,7,8-tetrahydronaphthalen-2-yl]-N-methylpyridin-3-amine

The title compound was prepared in 88% yield from Preparation 12aaccording to the general procedure for Preparation 9b. [M+H] calc'd forC₁₇H₂₁N₃, 268; found 268.

Preparation 12c: methyl3-({[(1R)-6-[methyl(pyridin-3-yl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 27% yield from Preparation 12baccording to the general procedure for Preparation 4d. [M+H] calc'd forC₂₄H₂₆N₄O₂, 403; found 403.

Example 12:3-({[(1R)-6-[methyl(pyridin-3-yl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 62% yield from Preparation 12caccording to the general procedure for Example 1. ¹H NMR (400 MHz,MeOD): δ 1.75-1.79 (1H, m), 1.93-1.99 (3H, m), 2.72-2.81 (2H, m),3.19-3.23 (1H, m), 3.33 (3H, s), 3.50-3.63 (2H, m), 6.91-6.97 (2H, m),7.30-7.38 (3H, m), 7.76-7.82 (2H, m), 7.92 (1H, br s), 8.04 (1H, br s),8.15 (1H, s). [M+H] calc'd for C₂₃H₂₄N₄O₂, 389; found 389.

Preparation 13a: tert-butylN-{[(1R)-6-[(6-methoxypyridin-3-yl)(methyl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}carbamate

The title compound was prepared in 64% yield from Preparation 6d and6-methoxy-N-methylpyridin-3-amine according to the general procedure forPreparation 9a. [M+H] calc'd for C₂₃H₃₁N₃O₃, 398; found 398.

Preparation 13b:N-[(5R)-5-(aminomethyl)-5,6,7,8-tetrahydronaphthalen-2-yl]-6-methoxy-N-methylpyridin-3-amine

The title compound was prepared in 98% yield from Preparation 13aaccording to the general procedure for Preparation 9b. [M+H] calc'd forC₁₈H₂₃N₃O, 298; found 298.

Example 13:3-({[(1R)-6-[(6-methoxypyridin-3-yl)(methyl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylicAcid

3-Fluoroisonicotinic acid (52 mg, 0.36 mmol), Preparation 13b (108 mg,0.36 mmol) and DIEA (64 μL, 0.36 mmol) were combined in DMA (2 mL), andthe solution was heated at 168° C. in a microwave for 1 h. The solutionwas concentrated and purified by prep-HPLC (35-85% ACN/water with 0.1%formic acid) to give 58 mg (39%) of the title compound as a pale yellowsolid. ¹H NMR (400 MHz, DMSO-d₆): δ 1.61-1.80 (4H, m), 2.61-2.67 (2H,m), 2.99-3.04 (1H, m), 3.18 (3H, s), 3.40-3.55 (2H, m), 3.83 (3H, s),6.54-6.60 (2H, m), 6.79 (1H, d, J=8.7 Hz), 7.15 (1H, d, J=8.5 Hz), 7.46(1H, d, J=8.7 Hz), 7.55 (1H, d, J=5.0 Hz), 7.72 (1H, br s), 7.82 (1H, d,J=5.0 Hz), 7.95 (1H, s), 8.34 (1H, s), 13.29 (1H, br s). [M+H] calc'dfor C₂₄H₂₆N₄O₃, 419; found 419.

Preparation 14a: (7-bromo-2H-chromen-4-yl)methanamine, Hydrochloride

To a solution of 7-bromochroman-4-one (5.00 g, 22.0 mmol) and ZnI₂ (30mg) in toluene (50 mL) was added TMSCN (4.36 g, 44.0 mmol), and themixture was heated at 60° C. overnight. The reaction mixture was cooledto rt, and a solution of LAH (20.0 mL, 2.4 M in THF, 44.0 mmol) wasadded slowly. The mixture was stirred at 40° C. for 2 h. The reactionwas quenched with the addition of EtOAc (10 mL) at 0° C., followed bywater (5 mL) and aqueous 10% NaOH (5 mL). The reaction mixture wasdiluted with EtOAc, dried (MgSO₄), filtered through Celite, andconcentrated to give 4.5 g (79%) of the crude4-(aminomethyl)-7-bromo-3,4-dihydro-2H-1-benzopyran-4-ol intermediate asa yellow oil.

To a solution of this intermediate (4.50 g, 17.4 mmol) in toluene (100mL) was added 4N HCl/dioxane (20 mL) solution, and the mixture wasstirred at reflux for 10 min. The mixture was cooled to rt andconcentrated. The residue was precipitated from cold EtOAc and collectedto give 3.6 g (75%) of the title compound as a yellow solid. [M+H]calc'd for C₁₀H₁₀BrNO, 240, 242; found 240, 242.

Preparation 14b: (7-bromo-3,4-dihydro-2H-1-benzopyran-4-yl)methanamine

To a solution of Preparation 14a (2.0 g, 7.2 mmol) in MeOH (20 mL) andAcOH (2 mL) was added Raney Ni (200 mg) at rt. The suspension wasstirred for overnight at under hydrogen at 50 psi. The reaction mixturewas filtered, and the pH was adjusted to 7-8 with sat. Na₂CO₃. Thesolution was dried (Na₂SO₄) and concentrated to give 1.32 g (75%) of thetitle compound as a brown oil. [M+H] Calc'd for C₁₀H₁₂BrNO, 242, 244;Found, 242, 244.

Preparation 14c: methyl3-{[(7-bromo-3,4-dihydro-2H-1-benzopyran-4-yl)methyl]amino}pyridine-4-carboxylate

The title compound was prepared in 44% yield from Preparation 9baccording to the general procedure for Preparation 1e. [M+H] Calc'd forC₁₇H₁₇BrN₂O₃, 377, 379; Found, 377, 379.

Example 14:3-{[(7-bromo-3,4-dihydro-2H-1-benzopyran-4-yl)methyl]amino}pyridine-4-carboxylicAcid

The title compound was prepared in 59% yield from Preparation 14caccording to the general procedure for Example 1. ¹H NMR (400 MHz,DMSO-d₆): δ 1.87-2.01 (2H, m), 3.10-3.14 (1H, m), 3.49-3.55 (1H, m),3.66-3.71 (1H, m), 4.16-4.23 (2H, m), 6.99-7.04 (2H, m), 7.27 (1H, d,J=8.0 Hz), 7.57 (1H, d, J=4.8 Hz), 7.85 (1H, d, J=5.2 Hz), 8.42 (1H, s).[M+H] Calc'd for C₁₆H₁₅BrN₂O₃, 363, 365; Found, 363, 365.

Preparation 15a: Methyl3-({[7-(phenylamino)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

A suspension of Preparation 14c (100 mg, 0.26 mmol), aniline (25.0 mg,0.26 mmol), Cs₂CO₃ (130 mg, 0.40 mmol), Pd(OAc)₂ (2.0 mg, 0.007 mmol)and BINAP (9.0 mg, 0.013 mmol) in toluene (10 mL) was stirred at 100° C.under N₂ overnight. The reaction was filtered and concentrated.Purification by silica gel chromatography (PE:EA=1:1) gave 54 mg (52%)of the title compound as a brown oil. [M+H] calc'd for C₂₃H₂₃N₃O₃, 390;found 390.

Example 15:3-({[7-(phenylamino)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 71% yield from Preparation 15aaccording to the general procedure for Example 1. ¹H NMR (400 MHz,DMSO-d₆): δ 1.86-1.88 (1H, m), 1.96-1.99 (1H, m), 3.04-3.05 (1H, m),3.3.43-3.48 (1H, m), 3.63-3.67 (1H, m), 4.12-4.17 (2H, m), 6.47 (1H, s),6.48-6.61 (1H, m), 6.78-6.82 (1H, m), 7.04 (2H, d, J=8.0 Hz), 7.11-7.23(3H, m), 7.58 (1H, d, J=4.8 Hz), 7.84 (1H, d, J=4.8 Hz), 8.08 (1H, s),8.38 (1H, s). [M+H] calc'd for C₂₂H₂₁N₃O₃, 376; found 376.

Preparation 16a: tert-butyl [(7-bromo-2H-chromen-4-yl)methyl]carbamate

To a solution of Preparation 14a (3.6 g, 13 mmol) in DMF (30 mL) wasadded TEA (5.5 mL, 39 mmol) and (Boc)₂O (3.40 g, 15.6 mmol). The mixturewas stirred at rt for 2 h. The reaction was concentrated and the residuewas purified by silica gel chromatography (PE:EtOAc=4:1) to give 3.19 g(72%) of the title compound as a yellow solid. ¹H NMR (400 MHz, CDCl₃):δ 6.97-7.03 (m, 3H), 5.72-5.75 (m, 1H), 4.76-4.79 (m, 2H), 4.67 (br s,1H), 4.08-4.15 (m, 2H), 1.45 (s, 9H). [M+H] calc'd for C₁₅H₁₈BrNO₃, 340,342; found 340, 342.

Preparation 16b: Tert-ButylN-{[7-(1,2,3,4-tetrahydroquinolin-1-yl)-2H-chromen-4-yl]methyl}carbamate

To a solution of Preparation 16a (500 mg, 1.47 mmol) in THF (15 mL) wasadded 1,2,3,4-tetrahydroquinoline (215 mg, 1.62 mmol), Cs₂CO₃ (719 g,2.21 mmol), BINAP (220 mg, 0.35 mmol) and Pd(OAc)₂ (40 mg, 0.18 mmol).The mixture was refluxed for overnight under nitrogen. The mixture wasfiltered and concentrated, and the residue was purified by silica gelchromatography (PE:EtOAc=5:1) to give 360 mg (62%) of the title compoundas a yellow oil. [M+H] calc'd for C₂₄H₂₈N₂O₃, 393; found 393.

Preparation 16c:[7-(1,2,3,4-tetrahydroquinolin-1-yl)-2H-chromen-4-yl]methanamine,Hydrochloride

A solution of Preparation 16b (360 mg, 0.918 mmol) in 4N HCl/EtOAc (20mL) was stirred overnight at rt. The mixture was concentrated to givethe crude title compound as a yellow solid. [M+H] calc'd for C₁₉H₂₀N₂O,293; found 293.

Preparation 16d:[7-(1,2,3,4-tetrahydroquinolin-1-yl)-3,4-dihydro-2H-1-benzopyran-4-yl]methanamine

To a solution of Preparation 16c (300 mg, 0.913 mmol) in MeOH (20 mL)and conc. HCl (one drop) was added 10% Pd/C (30 mg) under N₂. Thesuspension was stirred at rt under 50 psi of hydrogen overnight. Thereaction mixture was filtered, adjusted to pH=7˜8 with sat. K₂CO₃, dried(Na₂SO₄), and concentrated to give 240 mg (90%) of the title compound asa yellow oil. [M+H] calc'd for C₁₉H₂₂N₂O, 295; found 295.

Preparation 16e: methyl3-({[7-(1,2,3,4-tetrahydroquinolin-1-yl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

To a solution of Preparation 16d (240 mg, 0.816 mmol) in toluene (10 mL)was added methyl 3-bromoisonicotinate (176 mg, 0.816 mmol), Pd₂(dba)₃(15 mg, 0.016 mmol), Xantphos (29 mg, 0.049 mmol) and Cs₂CO₃ (373 mg,1.14 mmol). The mixture was heated to reflux under nitrogen overnight.The mixture was filtered and concentrated, and the residue was purifiedby silica gel chromatography (PE:EtOAc=2:1) to give 90 mg (26%) of thetitle compound as a yellow oil. [M+H] calc'd for C₂₆H₂₇N₃O₃, 430; found430.

Example 16:3-({[7-(1,2,3,4-tetrahydroquinolin-1-yl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 86% yield from Preparation 16faccording to the general procedure for Example 1. ¹H NMR (400 MHz,DMSO-d₆): δ 1.87-2.02 (4H, m), 2.75 (2H, t, J=6.0 Hz), 3.08-3.12 (1H,m), 3.51-3.68 (3H, m), 3.68-3.72 (1H, m), 4.13-4.23 (2H, m), 6.58 (1H,s), 6.65 (2H, d, J=7.6 Hz), 6.70-6.73 (1H, m), 6.89 (1H, t, J=7.2 Hz),7.00 (1H, d, J=7.2 Hz), 7.28 (1H, d, J=8.4 Hz), 7.58 (1H, d, J=4.8 Hz),7.84 (1H, d, J=5.2 Hz), 8.41 (1H, s). [M+H] calc'd for C₂₅H₂₅N₃O₃, 416;found 416.

Preparation 17a: Tert-ButylN-{[7-(2,3-dihydro-1H-indol-1-yl)-2H-chromen-4-yl]methyl}carbamate

The title compound was prepared in 59% yield from Preparation 16a andindoline according to the general procedure for Preparation 16c. [M+H]calc'd for C₂₃H₂₆N₂O₃, 379; found 379.

Preparation 17b:[7-(2,3-dihydro-1H-indol-1-yl)-2H-chromen-4-yl]methanamine,Hydrochloride

The title compound was prepared in 84% yield from Preparation 17aaccording to the general procedure for Preparation 16c. [M+H] calc'd forC₁₈H₁₈N₂O, 279; found 279.

Preparation 17c:[7-(2,3-dihydro-1H-indol-1-yl)-3,4-dihydro-2H-1-benzopyran-4-yl]methanamine

The title compound was prepared in 86% yield from Preparation 17baccording to the general procedure for Preparation 16d. [M+H] calc'd forC₁₈H₂₀N₂O, 281; found 281.

Preparation 17d: methyl3-({[7-(2,3-dihydro-1H-indol-1-yl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

To a solution of Preparation 17c (350 mg, 1.25 mmol) in DMA (6 mL) wasadded methyl 3-fluoroisonicotinate (195 mg, 1.25 mmol), and the reactionmixture was stirred at 170° C. for 1 h in a microwave. The reactionmixture was poured into water and extracted with EtOAc. Organics werewashed with brine, dried (Na₂SO₄) and concentration. Purification bysilica gel chromatography (PE:EtOAc=2:1) gave 79 mg (15%) of the titlecompound as a yellow gum. [M+H] calc'd for C₂₅H₂₅N₃O₃, 416; found 416.

Example 17:3-({[7-(2,3-dihydro-1H-indol-1-yl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 43% yield from Preparation 17daccording to the general procedure for Example 1. ¹H NMR (400 MHz,DMSO-d₆): δ 1.87-1.90 (1H, m), 1.97-2.01 (1H, m), 3.03-3.09 (3H, m),3.43-3.48 (1H, m), 3.63-3.68 (1H, m), 3.86 (2H, t, J=9.0 Hz), 4.13-4.21(2H, m), 6.58 (1H, s), 6.67-6.71 (1H, m), 6.77-6.80 (1H, m), 7.02-7.05(2H, m), 7.15 (1H, d, J=7.2 Hz), 7.26 (1H, d, J=8.4 Hz), 7.56 (1H, d,J=4.8 Hz), 7.81 (1H, d, J=5.2 Hz), 8.35 (1H, s). [M+H] calc'd forC₂₄H₂₃N₃O₃, 402; found 402.

Preparation 18a: 7-bromo-2H-chromene-4-carboxamide

To a solution of 7-bromochroman-4-one (2.0 g, 8.8 mmol) and AlCl₃ (118mg, 0.9 mmol) in toluene (10 mL) was added TMSCN (1.3 mL, 9.7 mmol). Thesolution was stirred at 40° C. for 1.5 h. The reaction was cooled to rt,and H₂SO₄ (1.0 mL) was added, followed by AcOH (13 mL) and more H₂SO₄(4.3 mL). The reaction was heated to 130° C. and stirred for 6 h. Thereaction was cooled, poured over H₂O (100 mL) and filtered. The filtercake dissolved in THF (50 mL) and filtered. The combined organicsolutions were concentrated to give 1.0 g (45%) of the crude titlecompound as an off-white solid. [M+H] calc'd for C₁₀H₈BrNO₂, 254, 256;found 254, 256.

Preparation 18b: (4R)-7-bromo-3,4-dihydro-2H-1-benzopyran-4-carboxamide

To a solution of Preparation 18a (6.0 g, 23.6 mmol) in MeOH (70 mL) andTHF (70 mL) was added Ru(OAc)₂[s-binap] (100 mg). The mixture was heatedat 80° C. overnight with 5.0 MPa H₂. The solution was concentrated toget the crude title compound (ee>90%). This was re-crystallized fromEtOAc to give 3.5 g (58%, ee>95%) as a white solid. [M+H] calc'd forC₁₀H₁₀BrNO₂, 256, 258; found 256, 258. Analytical Column: Chiralcel:AS-H, Mobile phase: CO₂:MeOH=70:30.

Preparation 18c:[(4R)-7-bromo-3,4-dihydro-2H-1-benzopyran-4-yl]methanamine

To a solution of Preparation 18b (500 mg, 2.0 mmol) in THF (10 mL) wasadded BH₃.THF (9.8 mL, 1.0 M, 9.8 mmol) at rt. The mixture was heated at45° C. for 3 h. The reaction was diluted with water (10 mL), basified topH 9 with sat. Na₂CO₃, and then extracted with EtOAc (3×50 mL). Organicswere washed with brine (50 mL), dried (Na₂SO₄), and concentrated to give500 mg of the crude title compound as a yellow oil. [M+H] calc'd forC₁₀H₁₂BrNO, 242, 244; found 242, 244.

Preparation 18d: tert-butylN-{[(4R)-7-bromo-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}carbamate

To a solution of Preparation 18c (2.0 mmol) and TEA (0.8 mL, 5.9 mmol)in DCM (10 mL) was added Boc₂O (510 mg, 2.3 mmol) at 0° C., and thereaction was stirred at rt overnight. The solution was concentrated andpurified by silica gel chromatography (PE:EtOAc=10:1) to give 270 mg(41%) of the title compound as a yellow oil. [M+H] calc'd forC₁₅H₂₀BrNO₃, 342, 344; found 342, 344.

Preparation 18e: tert-butylN-{[(4R)-7-[methyl(phenyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}carbamate

The title compound was prepared in 57% yield from Preparation 18d andN-methylaniline according to the general procedure for Preparation 6e.[M+H] calc'd for C₂₂H₂₈N₂O₃, 369; found 369.

Preparation 18f:(4R)-4-(aminomethyl)-N-methyl-N-phenyl-3,4-dihydro-2H-1-benzopyran-7-amine

The title compound was prepared in quantitative yield from Preparation18e according to the general procedure for Preparation 6f. [M+H] calc'dfor C₁₇H₂₀N₂O, 269; found 269.

Preparation 18g: methyl3-({[(4R)-7-[methyl(phenyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 68% yield from Preparation 18faccording to the general procedure for Preparation 16f. [M+H] calc'd forC₂₄H₂₅N₃O₃, 404; found 404.

Example 18:3-({[(4R)-7-[methyl(phenyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 32% yield from Preparation 18gaccording to the general procedure for Example 1. ¹H NMR (400 MHz,DMSO-d₆): δ 1.87-1.88 (1H, m), 1.96-1.97 (1H, m), 3.06-3.09 (1H, m),3.20 (3H, s), 3.44-3.52 (1H, m), 3.64-3.66 (1H, m), 4.12-4.18 (2H, m),6.36 (1H, d, J=2.1 Hz), 6.48 (1H, d, J=8.4 Hz), 6.91-7.01 (3H, m),7.17-7.29 (3H, m), 7.56 (1H, d, J=5.1 Hz), 7.83 (1H, d, J=5.1 Hz), 8.40(1H, s). [M+H] calc'd for C₂₃H₂₃N₃O₃, 390; found 390.

Preparation 19a: Tert-ButylN-{[(4R)-7-[(2-fluorophenyl)(methyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}carbamate

The title compound was prepared in 65% yield from Preparation 18d and2-fluoro-N-methylaniline according to the general procedure forPreparation 6e. [M+H] calc'd for C₂₂H₂₇FN₂O₃, 387; found 387.

Preparation 19b:(4R)-4-(aminomethyl)-N-(2-fluorophenyl)-N-methyl-3,4-dihydro-2H-1-benzopyran-7-amine

The title compound was prepared in quantitative yield from Preparation19a according to the general procedure for Preparation 6f. [M+H] calc'dfor C₁₇H₁₉FN₂O, 287; found 287.

Preparation 19c: methyl3-({[(4R)-7-[(2-fluorophenyl)(methyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 50% yield from Preparation 19baccording to the general procedure for Preparation 16e. [M+H] calc'd forC₂₄H₂₄FN₃O₃, 422; found 422.

Example 19:3-({[(4R)-7-[(2-fluorophenyl)(methyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 88% yield from Preparation 19caccording to the general procedure for Example 1. ¹H NMR (400 MHz,DMSO-d₆): δ 1.81-1.85 (1H, m), 1.93-1.99 (1H, m), 2.99-3.02 (1H, m),3.18 (3H, s), 3.41-3.44 (1H, m), 3.58-3.63 (1H, m), 4.08-4.14 (2H, m),6.04 (1H, s), 6.18 (1H, dd, J=1.2, 7.2 Hz), 7.10 (1H, d, J=8.4 Hz),7.24-7.34 (4H, m), 7.56 (1H, d, J=5.2 Hz), 7.82 (1H, d, J=4.8 Hz), 8.35(1H, s). [M+H] calc'd for C₂₃H₂₂FN₃O₃, 408; found 408.

Preparation 20a: Tert-ButylN-{[(4R)-7-[(3-fluorophenyl)(methyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}carbamate

The title compound was prepared in 83% yield from Preparation 18d and3-fluoro-N-methylaniline according to the general procedure forPreparation 6e. [M+H] calc'd for C₂₂H₂₇FN₂O₃, 387; found 387.

Preparation 20b:(4R)-4-(aminomethyl)-N-(3-fluorophenyl)-N-methyl-3,4-dihydro-2H-1-benzopyran-7-amine

The title compound was prepared in quantitative yield from Preparation20a according to the general procedure for Preparation 6f. [M+H] calc'dfor C₁₇H₁₉FN₂O, 287; found 287.

Preparation 20c: Methyl3-({[(4R)-7-[(3-fluorophenyl)(methyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 12% yield from Preparation 20baccording to the general procedure for Preparation 16e. [M+H] calc'd forC₂₄H₂₄FN₃O₃, 422; found 422.

Example 20:3-({[(4R)-7-[(3-fluorophenyl)(methyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 46% yield from Preparation 20caccording to the general procedure for Example 1. ¹H NMR (400 MHz,THF-d₈): δ 8.30 (s, 1H), 7.74 (brs, 2H), 7.48 (d, J=4.0 Hz, 1H), 7.14(d, J=8.0 Hz, 1H), 7.03-6.97 (m, 1H), 6.59-6.45 (m, 4H), 6.36 (t, J=8.0Hz, 1H), 4.13-4.02 (m, 2H), 3.65-3.59 (m, 1H), 3.42-3.34 (m, 1H), 3.14(s, 3H), 3.08-3.02 (m, 1H), 2.00-1.86 (m, 2H). [M+H] calc'd forC₂₃H₂₂FN₃O₃, 408; found 408.

Preparation 21a: Tert-ButylN-{[(4R)-7-[(4-fluorophenyl)(methyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}carbamate

The title compound was prepared in 55% yield from Preparation 18d and4-fluoro-N-methylaniline according to the general procedure forPreparation 6e. [M+H] calc'd for C₂₂H₂₇FN₂O₃, 387; found 387.

Preparation 21b:(4R)-4-(aminomethyl)-N-(4-fluorophenyl)-N-methyl-3,4-dihydro-2H-1-benzopyran-7-amine

The title compound was prepared in quantitative yield from Preparation21a according to the general procedure for Preparation 6f. [M+H] calc'dfor C₁₇H₁₉FN₂O, 287; found 287.

Preparation 21c: Methyl3-({[(4R)-7-[(4-fluorophenyl)(methyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 83% yield from Preparation 21baccording to the general procedure for Preparation 16e. [M+H] calc'd forC₂₄H₂₄FN₃O₃, 422; found 422.

Example 21:3-({[(4R)-7-[(4-fluorophenyl)(methyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 83% yield from Preparation 21caccording to the general procedure for Example 1. ¹H NMR (400 MHz,DMSO-d₆): δ 1.82-1.87 (1H, m), 1.94-1.99 (1H, m), 3.03-3.06 (1H, m),3.17 (3H, s), 3.43-3.49 (1H, m), 3.63-3.67 (1H, m), 4.09-4.20 (2H, m),6.26 (1H, s), 6.38 (1H, d, J=8.4 Hz), 7.04-7.08 (2H, m), 7.11-7.16 (3H,m), 7.56 (1H, d, J=5.2 Hz), 7.83 (1H, d, J=4.8 Hz), 8.39 (1H, s). [M+H]calc'd for C₂₃H₂₂FN₃O₃, 408; found 408.

Preparation 22a: Tert-ButylN-{[(4R)-7-[methyl(4-methylphenyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}carbamate

The title compound was prepared in 45% yield from Preparation 18d and4-methyl-N-methylaniline according to the general procedure forPreparation 6e. [M+H] calc'd for C₂₃H₃₀N₂O₃, 383; found 383.

Preparation 22b:(4R)-4-(aminomethyl)-N-methyl-N-(4-methylphenyl)-3,4-dihydro-2H-1-benzopyran-7-amine

The title compound was prepared in quantitative yield from Preparation22a according to the general procedure for Preparation 6f. [M+H] calc'dfor C₁₈H₂₂N₂O, 283; found 283.

Preparation 22c: Methyl3-({[(4R)-7-[methyl(4-methylphenyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 29% yield from Preparation 22baccording to the general procedure for Preparation 16e. [M+H] calc'd forC₂₅H₂₇N₃O₃, 418; found 418.

Example 22:3-({[(4R)-7-[methyl(4-methylphenyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 79% yield from Preparation 22caccording to the general procedure for Example 1. ¹H NMR (400 MHz,DMSO-d₆): δ 1.84-1.86 (1H, m), 1.95-1.99 (1H, m), 2.26 (3H, s),3.02-3.05 (1H, m), 3.16 (3H, s), 3.42-3.48 (1H, m), 3.62-3.66 (1H, m),4.08-4.16 (2H, m), 6.25 (1H, s), 6.38-6.40 (1H, m), 6.95 (2H, d, J=8.0Hz), 7.10-7.14 (3H, m), 7.56 (1H, d, J=5.2 Hz), 7.84 (1H, d, J=5.2 Hz),8.38 (1H, s). [M+H] calc'd for C₂₄H₂₅N₃O₃, 404; found 404.

Preparation 23a: Tert-ButylN-{[(4R)-7-[(4-chlorophenyl)(methyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}carbamate

The title compound was prepared in 65% yield from Preparation 18d and4-chloro-N-methylaniline according to the general procedure forPreparation 6e. [M+H] calc'd for C₂₂H₂₇ClN₂O₃, 403; found 403.

Preparation 23b:(4R)-4-(aminomethyl)-N-(4-chlorophenyl)-N-methyl-3,4-dihydro-2H-1-benzopyran-7-amine

The title compound was prepared in quantitative yield from Preparation23a according to the general procedure for Preparation 6f. [M+H] calc'dfor C₁₇H₁₉ClN₂O, 303; found 303.

Preparation 23c: Methyl3-({[(4R)-7-[(4-chlorophenyl)(methyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 18% yield from Preparation 21baccording to the general procedure for Preparation 16e. [M+H] calc'd forC₂₄H₂₄ClN₃O₃, 438; found 438.

Example 23:3-({[(4R)-7-[(4-chlorophenyl)(methyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 51% yield from Preparation 23caccording to the general procedure for Example 1. ¹H NMR (400 MHz,DMSO-d₆): δ 8.39 (s, 1H), 7.84 (d, J=4.8 Hz, 1H), 7.56 (d, J=4.8 Hz,1H), 7.27-7.23 (m, 3H), 6.92 (d, J=8.8 Hz, 2H), 6.56 (dd, J=8.0 Hz, 2.0Hz, 1H), 6.45 (d, J=2.0 Hz, 1H), 4.23-4.12 (m, 2H), 3.71-3.66 (m, 1H),3.52-3.46 (m, 1H), 3.20 (s, 3H), 3.11-3.07 (m, 1H), 2.02-1.95 (m, 1H),1.89-1.86 (m, 1H). [M+H] calc'd for C₂₃H₂₂ClN₃O₃, 424; found 424.

Preparation 24a: Tert-ButylN-{[(4R)-7-[ethyl(phenyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}carbamate

The title compound was prepared in 68% yield from Preparation 18d andN-ethylaniline according to the general procedure for Preparation 6e.[M+H] calc'd for C₂₃H₃₀N₂O₃, 383; found 383.

Preparation 24b:(4R)-4-(aminomethyl)-N-ethyl-N-phenyl-3,4-dihydro-2H-1-benzopyran-7-amine

The title compound was prepared in quantitative yield from Preparation24a according to the general procedure for Preparation 6f. [M+H] calc'dfor C₁₈H₂₂N₂O, 283; found 283.

Preparation 24c: Methyl3-({[(4R)-7-[ethyl(phenyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 33% yield from Preparation 22baccording to the general procedure for Preparation 16e. [M+H] calc'd forC₂₅H₂₇N₃O₃, 418; found 418.

Example 24:3-({[(4R)-7-[ethyl(phenyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 58% yield from Preparation 24caccording to the general procedure for Example 1. ¹H NMR (400 MHz,DMSO-d₆): δ 1.10 (3H, t, J=6.8 Hz), 1.83-1.87 (1H, m), 1.95-2.00 (1H,m), 3.05-3.08 (1H, m), 3.45-3.51 (1H, m), 3.65-3.72 (3H, m), 4.10-4.18(2H, m), 6.33 (1H, s), 6.4 (1H, d, J=8.0 Hz), 6.91-6.98 (3H, m), 7.17(1H, d, J=8.4 Hz), 7.26 (2H, t, J=7.6 Hz), 7.57 (1H, d, J=4.4 Hz), 7.84(1H, d, J=4.8 Hz), 8.40 (1H, s). [M+H] calc'd for C₂₄H₂₅N₃O₃, 404; found404.

Preparation 25a: 2-hydroxy-5,6,7,8-tetrahydroquinolin-5-one

A mixture of 3-amino-2-cyclohexen-1-one (25.0 g, 224.9 mmol) and methylpropiolate (23.6 g, 281 mmol) was heated to reflux for 1 h. The mixturewas cooled and the solid was collected by filtration, washing with THF,to give 7.8 g (21%) of the title compound as a yellow solid. [M+H]calc'd for C₉H₉NO₂, 164; found 164.

Preparation 25b: 2-chloro-5,6,7,8-tetrahydroquinolin-5-one

To the suspension of Preparation 25a (7.8 g, 47.7 mmol) in ACN (120 mL)was added POCl₃ (14.6 g, 95.3 mmol) dropwise. The reaction mixture washeated to reflux for 2 h and then concentrated. The residue wasdissolved in H₂O, basified to pH 8 with 2N NaOH, and extracted withEtOAc. Organics were concentrated and purified by silica gelchromatography (PE:EtOAc=4:1) to give 7.1 g (82%) of the title compoundas an off-white solid. [M+H] calc'd for C₉H₈ClNO, 182; found 182.

Preparation 25c: 2-phenyl-5,6,7,8-tetrahydroquinolin-5-one

The suspension of Preparation 25b (0.82 g, 4.5 mmol), phenylboronic acid(1.1 g, 9.1 mmol), Pd(Ph₃P)₄ (0.25 g, 0.23 mmol), and Na₂CO₃ (1.5 g,13.6 mmol) in dioxane (30 mL) and H₂O (2 mL) was heated to refluxovernight under N₂. The reaction mixture was cooled, filtered, andconcentrated. Purification by silica gel chromatography (PE:EtOAc=9:1)gave 1.1 g (85%) of the title compound as a white solid. [M+H] calc'dfor C₁₅H₁₃NO₂, 224; found 224.

Preparation 25d: (2-phenyl-7,8-dihydroquinolin-5-yl)methanamine, H₂SO₄Salt

To a solution of Preparation 25c (1.0 g, 4.6 mmol) and ZnI₂ (20 mg) intoluene (20 mL) was added TMSCN (0.91 g, 9.2 mmol) at rt. The solutionwas heated at 110° C. overnight. The reaction was cooled to 0° C., andLAH (3.9 mL, 2.4 M, 9.2 mmol) was added, and the reaction stirred for 2h. The reaction was quenched with addition of EtOAc (20 mL) at 0° C.,followed by water (0.4 mL) and aqueous 10% NaOH (0.4 mL). The mixturewas filtered and concentrated. The resulting solid was washed with MTBEto give 0.55 g (47%) of the5-(aminomethyl)-2-phenyl-5,6,7,8-tetrahydroquinolin-5-ol intermediatedas a brown solid. To a solution of5-(aminomethyl)-2-phenyl-5,6,7,8-tetrahydroquinolin-5-ol (0.55 g, 2.2mmol) in toluene (80 mL) was added conc. H₂SO₄ (24 drops), and thesolution was stirred at 150° C. under a Dean-Stark condenser. Thesolution was cooled to rt and concentrated to give the crude titlecompound. [M+H] calc'd for C₁₆H₁₆N₂, 237; found 237.

Preparation 25e: (2-phenyl-5,6,7,8-tetrahydroquinolin-5-yl)methanamine

To a solution of Preparation 25d (2.2 mmol) in MeOH (20 mL) and AcOH (2mL) under N₂ was added 10% Pd/C (270 mg) at rt. The mixture was heatedto 50° C. overnight under H₂. The reaction was filtered through Celiteand concentrated. The residue was diluted with EtOAc, washed with sat.K₂CO₃ solution, dried (Na₂SO₄), and concentrated to 0.52 g of the crudetitle compound as a brown oil. [M+H] calc'd for C₁₆H₁₈N₂, 239; found239.

Preparation 25f: Methyl3-({[(4R)-7-[ethyl(phenyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 54% yield from Preparation 25eaccording to the general procedure for Preparation 4d. [M+H] Calc'd forC₂₃H₂₃N₃O₂, 374; Found, 374.

Example 25:3-({[(4R)-7-[ethyl(phenyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 41% yield from Preparation 25faccording to the general procedure for Example 1. ¹H NMR (400 MHz,DMSO-d₆): δ 1.79-2.00 (m, 4H), 2.88-2.94 (m, 2H), 3.22-3.23 (m, 1H),3.50-3.56 (m, 1H), 3.64-3.68 (m, 1H), 7.41 (d, J=7.6 Hz, 1H), 7.47 (t,J=7.6 Hz, 2H), 7.57 (d, J=4.8 Hz, 1H), 7.72 (d, J=8.0 Hz, 1H), 7.81 (d,J=8.0 Hz, 1H), 7.85 (d, J=4.8 Hz, 1H), 8.05 (d, J=7.6 Hz, 2H), 8.43 (s,1H). [M+H] Calc'd for C₂₂H₂₁N₃O₂, 360; Found, 360.

Preparation 26a:2-[methyl(phenyl)amino]-5,6,7,8-tetrahydroquinolin-5-one

To a solution of Preparation 25b (4.5 g, 24.7 mmol) in toluene (100 mL)was added N-methylaniline (5.3 g, 49.4 mmol), Pd₂(dba)₃ (456 mg, 0.49mmol), Xantphos (0.86 g, 1.48 mmol) and Cs₂CO₃ (11.3 g, 34.6 mmol). Themixture was heated to reflux under nitrogen overnight. The mixture wasfiltered and concentrated. The residue was purified by silica gelchromatography (PE:EtOAc=20:1 to 10:1) to give 1.6 g (26%) of the titlecompound as an off-white solid. [M+H] calc'd for C₁₆H₁₆N₂O, 253; found253.

Preparation 26b:5-(aminomethyl)-N-methyl-N-phenyl-7,8-dihydroquinolin-2-amine,Hydrochloride

The title compound was prepared in 51% yield from Preparation 26aaccording to the general procedure for Preparation 25d. [M+H] calc'd forC₁₇H₁₉N₂, 266; found 266.

Preparation 26c:5-(aminomethyl)-N-methyl-N-phenyl-5,6,7,8-tetrahydroquinolin-2-amine

The title compound was prepared in quantitative yield from Preparation26b according to the general procedure for Preparation 25e. [M+H] calc'dfor C₁₇H₂₁N₂, 268; found 268.

Preparation 26d: Methyl3-[({2-[methyl(phenyl)amino]-5,6,7,8-tetrahydroquinolin-5-yl}methyl)amino]pyridine-4-carboxylate

The title compound was prepared in 30% yield from Preparation 26caccording to the general procedure for Preparation 4d. [M+H] Calc'd forC₂₄H₂₆N₄O₂, 403; Found, 403.

Example 26:3-[({2-[methyl(phenyl)amino]-5,6,7,8-tetrahydroquinolin-5-yl}methyl)amino]pyridine-4-carboxylicAcid

The title compound was prepared in 47% yield from Preparation 26daccording to the general procedure for Example 1. ¹H NMR (400 MHz,DMSO-d₆): δ 1.72-1.93 (m, 4H), 2.67-2.73 (m, 2H), 2.98-3.02 (m, 1H),3.37 (s, 3H), 3.40-3.43 (m, 1H), 3.50-3.54 (m, 1H), 6.35 (d, J=8.4 Hz,1H), 7.18 (t, J=7.2 Hz, 1H), 7.25 (d, J=7.2 Hz, 2H), 7.39 (d, J=7.2 Hz,2H), 7.41 (d, J=8.4 Hz, 1H), 7.55 (d, J=4.8 Hz, 1H), 7.82 (d, J=4.8 Hz,1H), 8.34 (s, 1H). [M+H] Calc'd for C₂₃H₂₄N₄O₂, 389; Found, 389.

Preparation 27a:7-[4-(trifluoromethyl)phenyl]-3,4-dihydro-2H-1-benzopyran-4-one

To a solution of 7-bromo-4-chromanone (1.0 g, 4.4 mmol) in DMF (15 mL)was added [4-(trifluoromethyl)phenyl]boronic acid (1.25 g, 6.6 mmol),Pd(PPh₃)₄ (580 mg, 0.5 mmol) and K₂CO₃ (1.22 g, 8.8 mmol). The mixturewas stirred at 105° C. for 4 h under nitrogen. The mixture was filteredand concentrated, and the residue was purified by silica gelchromatography (PE:EtOAc=4:1) to give 830 mg (61%) of the title compoundas white solid. [M+H] Calc'd for C₁₆H₁₁F₃O₂, 293; Found, 293.

Preparation 27b:{7-[4-(trifluoromethyl)phenyl]-2H-chromen-4-yl}methanamine,Hydrochloride

The title compound was prepared in 41% yield from Preparation 27aaccording to the general procedure for Preparation 3a. [M+H] Calc'd forC₁₇H₁₄F₃NO, 306; Found, 306.

Preparation 27c:{7-[4-(trifluoromethyl)phenyl]-3,4-dihydro-2H-1-benzopyran-4-yl}methanamine

The title compound was prepared in 80% yield from Preparation 27baccording to the general procedure for Preparation 3e. [M+H] Calc'd forC₁₇H₁₆F₃NO, 308; Found, 308.

Preparation 27d: Methyl3-[({7-[4-(trifluoromethyl)phenyl]-3,4-dihydro-2H-1-benzopyran-4-yl}methyl)amino]pyridine-4-carboxylate

To a solution of Preparation 27c (260 mg, 0.85 mmol) in DMA (10 mL) wasadded methyl 3-fluoroisonicotinate (330 mg, 2.2 mmol) at rt. Thereaction mixture was stirred at 170° C. for 1 h in a microwave. Thereaction mixture was poured into water, and extracted with EtOAc. Theorganic layer was washed with brine, dried (Na₂SO₄), and concentrated.Purification by silica gel chromatography gave 28 mg (7%) of the titlecompound as yellow solid. [M+H] Calc'd for C₂₄H₂₁F₃N₂O₃, 443; Found,443.

Example 27:3-[({7-[4-(trifluoromethyl)phenyl]-3,4-dihydro-2H-1-benzopyran-4-yl}methyl)amino]pyridine-4-carboxylicAcid

The title compound was prepared in 59% yield from Preparation 38aaccording to the general procedure for Example 1. ¹H NMR (400 MHz,DMSO-d₆): δ 1.94-1.96 (1H, m), 2.02-2.03 (1H, m), 3.17-3.22 (1H, m),3.50-3.56 (1H, m), 3.71-3.74 (1H, m), 4.21-4.27 (2H, m), 7.14 (1H, s),7.23 (1H, d, J=7.2 Hz), 7.45 (1H, d, J=8.4 Hz), 7.58 (1H, d, J=4.8 Hz),7.77-7.87 (5H, m), 8.41 (1H, s). [M+H] Calc'd for C₂₃H₁₉F₃N₂O₃, 429;Found, 429.

Preparation 28a: 7-(furan-3-yl)-3,4-dihydro-2H-1-benzopyran-4-one

To a solution of 6-bromo-1,2,3,4-tetrahydronaphthalen-1-one (1.5 g, 6.6mmol) in dioxane (6 mL) was added2-(furan-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.92 g, 9.9mmol), Pd(dppf)Cl₂.DCM (540 mg, 0.66 mmol) and sat. NaHCO₃ (2 mL). Themixture was stirred at 100° C. for 4 h under nitrogen. The mixture wascooled to rt and diluted with EtOAc, filtered, and concentrated. Theresidue was purified by silica gel chromatography (4:1 PE:EtOAc) to give1.18 g (83%) of the title compound as white solid. ¹H NMR (400 MHz,CDCl₃): δ 2.82 (2H, t, J=6.2 Hz), 4.56 (2H, t, J=6.4 Hz), 6.71 (1H, s),7.07 (1H, s), 7.14 (1H, d, J=8.4 Hz), 7.50 (1H, s), 7.81 (1H, s), 7.88(1H, d, J=8.4 Hz). [M+H] Calc'd for C₁₃H₁₀O₃, 215; Found, 215.

Preparation 28b: [7-(furan-3-yl)-2H-chromen-4-yl]methanamine,Hydrochloride

The title compound was prepared in 87% yield from Preparation 28aaccording to the general procedure for Preparation 3a. [M+H] Calc'd forC₁₄H₁₃NO₂, 228; Found, 228.

Preparation 28c:[7-(furan-3-yl)-3,4-dihydro-2H-1-benzopyran-4-yl]methanamine

The title compound was prepared in 57% yield from Preparation 28baccording to the general procedure for Preparation 3e. [M+H] Calc'd forC₁₄H₁₅NO₂, 230; Found, 230.

Preparation 28d: Methyl3-({[7-(furan-3-yl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 14% yield from Preparation 28caccording to the general procedure for Preparation 1e. [M+H] Calc'd forC₂₁H₂₀N₂O₄, 365; Found, 365.

Example 28:3-({[7-(furan-3-yl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 71% yield from Preparation 28daccording to the general procedure for Example 1. ¹H NMR (300 MHz,DMSO-d₆): δ 1.89-1.91 (1H, m), 1.97-2.00 (1H, m), 3.11-3.16 (1H, m),3.48-3.56 (1H, m), 3.67-3.72 (1H, m), 4.17-4.23 (2H, m), 6.92 (1H, s),7.03 (1H, s), 7.10 (1H, d, J=8.1 Hz), 7.29 (1H, d, J=8.1 Hz), 7.56 (1H,d, J=5.1 Hz), 7.70 (1H, s), 7.84 (1H, d, J=5.1 Hz), 8.14 (1H, s), 8.43(1H, s). [M+H] Calc'd for C₂₀H₁₈N₂O₄, 351; Found, 351.

Preparation 29a: 7-(3-methylphenyl)-3,4-dihydro-2H-1-benzopyran-4-one

To a suspension of 6-bromo-1,2,3,4-tetrahydronaphthalen-1-one (2.0 g,8.9 mmol), 3-methylbenzeneboronic acid (1.8 g, 13.2 mmol), Na₂CO₃ (2.8g, 26.4 mmol) in dioxane (40 mL) and water (2 mL) was added Pd(PPh₃)₄(509 mg, 0.4 mmol) at rt under N₂. The reaction was stirred at 100° C.overnight. The reaction was filtered and concentrated. Purification bysilica gel chromatography (PE:EtOAc=12:1) gave 2.0 g (96%) of the titlecompound as a white oil. ¹H NMR (300 MHz, CDCl₃): δ 2.44 (3H, s), 2.86(2H, t, J=6.6 Hz), 4.59 (2H, t, J=6.6 Hz), 7.20-7.29 (3H, m), 7.36-7.44(3H, m), 7.87 (1H, d, J=8.1 Hz). [M+H] Calc'd for C₁₆H₁₄O₂, 239; Found,239.

Preparation 29b: [7-(3-methylphenyl)-2H-chromen-4-yl]methanamine

The title compound was prepared in 29% yield from Preparation 29aaccording to the general procedure for Preparation 3a. [M+H] Calc'd forC₁₇H₁₇NO, 252; Found, 252.

Preparation 29c:[7-(3-methylphenyl)-3,4-dihydro-2H-1-benzopyran-4-yl]methanamine

The title compound was prepared in 99% yield from Preparation 29baccording to the general procedure for Preparation 3e. [M+H] Calc'd forC₁₇H₁₉NO, 254; Found, 254.

Preparation 29d: Methyl3-({[(4S)-7-(3-methylphenyl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate;and Preparation 30d: Methyl3-({[(4R)-7-(3-methylphenyl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

The racemate of the title compounds (200 mg) was prepared in 22% yieldfrom Preparation 29c according to the general procedure for Preparation1e. [M+H] Calc'd for C₂₄H₂₄N₂O₃, 389; Found, 389.

Separation by chiral HPLC (Column: Chiralcel IA Sum 4.6*250 mm, Mobilephase: Hex:EtOH=50:50; F: 1.0 mL/min; W: 230 nm; T: 30° C.) gave 50 mg(25%) of Preparation 30d (9.211 min) and 52 mg (26%) of Preparation 29d(11.640 min), each as a yellow oil.

Example 29:3-({[(4S)-7-(3-methylphenyl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 89% yield from Preparation 29daccording to the general procedure for Example 1. ¹H NMR (300 MHz,DMSO-d₆): δ 1.90-1.94 (1H, m), 2.00-2.04 (1H, m), 2.36 (3H, s),3.17-3.20 (1H, m), 3.51-3.58 (1H, m), 3.71-3.77 (1H, m), 4.21-4.25 (2H,m), 7.03 (1H, d, J=0.9 Hz), 7.13-7.16 (2H, m), 7.29-7.43 (4H, m), 7.58(1H, d, J=5.1 Hz), 7.86 (1H, d, J=5.1 Hz), 8.45 (1H, s). [M+H] Calc'dfor C₂₃H₂₂N₂O₃, 375; Found, 375.

Example 30:3-({[(4R)-7-(3-methylphenyl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 90% yield from Preparation 30daccording to the general procedure for Example 1. ¹H NMR (300 MHz,DMSO-d₆): δ 1.90-1.94 (1H, m), 2.00-2.04 (1H, m), 2.36 (3H, s),3.17-3.20 (1H, m), 3.51-3.58 (1H, m), 3.71-3.77 (1H, m), 4.21-4.25 (2H,m), 7.03 (1H, d, J=0.9 Hz), 7.13-7.16 (2H, m), 7.29-7.43 (4H, m), 7.58(1H, d, J=5.1 Hz), 7.86 (1H, d, J=5.1 Hz), 8.45 (1H, s). [M+H] Calc'dfor C₂₃H₂₂N₂O₃, 375; Found, 375.

Preparation 31a: 7-(4-methylphenyl)-3,4-dihydro-2H-1-benzopyran-4-one

The title compound was prepared in 95% yield from 4-methylbenzeneboronicacid according to the general procedure for Preparation 27a. ¹H NMR (400MHz, CDCl₃): δ 2.40 (3H, s), 2.82 (2H, t, J=6.6 Hz), 4.56 (2H, t, J=6.4Hz), 7.17 (1H, s), 7.23-7.27 (3H, m), 7.49 (2H, d, J=8.0 Hz), 7.92 (1H,d, J=8.4 Hz). [M+H] Calc'd for C₁₆H₁₄O₂, 239; Found, 239.

Preparation 31b: [7-(4-methylphenyl)-2H-chromen-4-yl]methanamine,Hydrochloride

The title compound was prepared in 51% yield from Preparation 31aaccording to the general procedure for Preparation 3a. [M+H] Calc'd forC₁₇H₁₇NO, 252; Found, 252.

Preparation 31c:[7-(4-methylphenyl)-3,4-dihydro-2H-1-benzopyran-4-yl]methanamine

The title compound was prepared in 72% yield from Preparation 31baccording to the general procedure for Preparation 3e. [M+H] Calc'd forC₁₇H₁₉NO, 254; Found, 254.

Preparation 31d: Methyl3-({[(4S)-7-(4-methylphenyl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate;and Preparation 32d: Methyl3-({[(4R)-7-(4-methylphenyl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

The racemate of the title compounds (370 mg) was prepared in 30% yieldfrom Preparation 29c according to the general procedure for Preparation1e. [M+H] Calc'd for C₂₄H₂₄N₂O₃, 389; Found, 389.

Separation by chiral HPLC (Column: Chiralcel IA, 250 mm*4.6 mm, Sum;Mobile phase: Hex:EtOH=50:50; F: 1.0 mL/min; W: 230 nm; T=30° C.) give160 mg (43%) of Preparation 32d (10.07 min) and 135 mg (36%) ofPreparation 31d (12.88 min), each as a yellow oil.

Example 31:3-({[(4S)-7-(4-methylphenyl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 59% yield from Preparation 31daccording to the general procedure for Example 1. ¹H NMR (300 MHz,DMSO-d₆): δ 1.90-1.92 (1H, m), 1.99-2.04 (1H, m), 2.32 (3H, s),3.20-3.25 (1H, m), 3.59-3.64 (1H, m), 3.73-3.77 (1H, m), 4.16-4.25 (2H,m), 7.03 (1H, s), 7.11 (1H, d, J=7.5 Hz), 7.22 (2H, d, J=7.5 Hz), 7.37(1H, d, J=7.8 Hz), 7.49 (2H, d, J=7.8 Hz), 8.03 (1H, d, J=5.7 Hz), 8.13(1H, d, J=5.4 Hz), 8.30 (1H, bs), 8.61 (1H, s).

[M+H] Calc'd for C₂₃H₂₂N₂O₃, 375; Found, 375.

Example 32:3-({[(4R)-7-(4-methylphenyl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 71% yield from Preparation 32daccording to the general procedure for Example 1. ¹H NMR (300 MHz,DMSO-d₆): δ 1.90-1.92 (1H, m), 1.99-2.04 (1H, m), 2.32 (3H, s),3.20-3.25 (1H, m), 3.59-3.64 (1H, m), 3.73-3.77 (1H, m), 4.16-4.25 (2H,m), 7.02 (1H, s), 7.11 (1H, d, J=8.1 Hz), 7.21 (2H, d, J=8.1 Hz), 7.36(1H, d, J=8.4 Hz), 7.48 (2H, d, J=7.8 Hz), 8.03 (1H, d, J=5.7 Hz), 8.14(1H, d, J=5.7 Hz), 8.30 (1H, bs), 8.61 (1H, s). [M+H] Calc'd forC₂₃H₂₂N₂O₃, 375; Found, 375.

Preparation 33a: 7-(thiophen-3-yl)-3,4-dihydro-2H-1-benzopyran-4-one

The title compound was prepared in 85% yield from 3-thienylboronic acidaccording to the general procedure for Preparation 27a. [M+H] Calc'd forC₁₃H₁₀O₂S, 231; Found, 231.

Preparation 33b: [7-(thiophen-3-yl)-2H-chromen-4-yl]methanamine,Hydrochloride

The title compound was prepared in 77% yield from Preparation 33aaccording to the general procedure for Preparation 3a. [M+H] Calc'd forC₁₄H₁₃NOS, 244; Found, 244.

Preparation 33c:[7-(thiophen-3-yl)-3,4-dihydro-2H-1-benzopyran-4-yl]methanamine

The title compound was prepared in 99% yield from Preparation 33baccording to the general procedure for Preparation 3e. [M+H] Calc'd forC₁₄H₁₅NOS, 246; Found, 246.

Preparation 33d: Methyl3-({[(4S)-7-(thiophen-3-yl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate;and Preparation 34d: Methyl3-({[(4R)-7-(thiophen-3-yl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

The racemate of the title compounds (250 mg) was prepared in 16% yieldfrom Preparation 33c according to the general procedure for Preparation1e.

Separation by chiral HPLC (Column: Chiralcel: AS 5 um 4.6*250 mm, Mobilephase: Hex:EtOH=80:20, F: 1.0 mL/min, W: 230 nm, T: 30° C.) gave 83 mg(33%) of Preparation 34d (9.489 min) and 76 mg (30%) of Preparation 33d(11.968 min), each as a yellow solid.

Example 33:3-({[(4S)-7-(thiophen-3-yl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 64% yield from Preparation 33daccording to the general procedure for Example 1. ¹H NMR (400 MHz,DMSO-d₆): δ 1.90-1.92 (1H, m), 1.99-2.03 (1H, m), 3.14-3.18 (1H, m),3.52-3.58 (1H, m), 3.71-3.75 (1H, m), 4.19-4.25 (2H, m), 7.14 (1H, s),7.22 (1H, d, J=8.0 Hz), 7.34 (1H, d, J=8.0 Hz), 7.52-7.62 (3H, m),7.85-7.87 (2H, m), 8.45 (1H, s). [M+H] Calc'd for C₂₀H₁₈N₂O₃S, 367;Found, 367.

Example 34:3-({[(4R)-7-(thiophen-3-yl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 62% yield from Preparation 34daccording to the general procedure for Example 1. ¹H NMR (400 MHz,DMSO-d₆): δ 1.92-1.93 (1H, m), 1.99-2.03 (1H, m), 3.16-3.17 (1H, m),3.55-3.57 (1H, m), 3.71-3.75 (1H, m), 4.20-4.24 (2H, m), 7.13 (1H, s),7.22 (1H, d, J=8.4 Hz), 7.34 (1H, d, J=8.0 Hz), 7.52-7.61 (3H, m),7.85-7.86 (2H, m), 8.44 (1H, s). [M+H] Calc'd for C₂₀H₁₈N₂O₃S, 367;Found, 367.

Preparation 35a: Tert-ButylN-{[7-(cyclohex-1-en-1-yl)-2H-chromen-4-yl]methyl}carbamate

To a solution of Preparation 3b (600 mg, 1.76 mmol) in dioxane (25 mL)was added compound 1-cyclohexen-yl-boronic acid pinacol ester (404 mg,1.94 mmol), Pd(PPh₃)₄ (204 mg, 1.76 mmol), Na₂CO₃ (8.0 mL, 2.0 mol/L, 14mmol). The mixture was stirred at 80° C. for overnight under nitrogen.The mixture was filtered and concentrated. The residue was purified bysilica gel chromatography (PE:EtOAc=5:1) to give 450 mg (75%) of thetitle compound as a light red solid. [M+H] Calc'd for C₂₁H₂₇NO₃, 342;Found, 342.

Preparation 35b: Tert-ButylN-[(7-cyclohexyl-3,4-dihydro-2H-1-benzopyran-4-yl)methyl]carbamate

The title compound was prepared in 88% yield from Preparation 35aaccording to the general procedure for Preparation 3e. [M+H] Calc'd forC₂₁H₃₁NO₃, 346; Found, 346.

Preparation 35c:(7-cyclohexyl-3,4-dihydro-2H-1-benzopyran-4-yl)methanamine

To a solution of Preparation 35b (400 mg, 1.16 mmol) in EtOAc (10 mL)was added EtOAc/HCl (10 mL, 1.0 M), and the reaction mixture was stirredat rt for 4 h. The reaction mixture was concentrated, and the residuewas taken up in sat. aq. K₂CO₃ (20 mL) and extracted with EtOAc (3×10mL). Organics were dried (Na₂SO₄) and concentrated to give 289 mg(quantitative) of the title compound as a pale brown oil. [M+H] Calc'dfor C₁₆H₂₃NO, 246; Found, 246.

Preparation 35d: Methyl3-({[(4R)-7-cyclohexyl-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 20% yield from Preparation 35caccording to the general procedure for Preparation 1e. [M+H] Calc'd forC₂₃H₂₈N₂O₃, 381; Found, 381.

Example 35:3-({[(4R)-7-cyclohexyl-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 48% yield from Preparation 35daccording to the general procedure for Example 1. ¹H NMR (300 MHz,DMSO-d₆): δ 1.31-1.37 (5H, m), 1.66-1.97 (7H, m), 2.36-2.39 (1H, m),3.06-3.08 (1H, m), 3.46-3.48 (1H, m), 3.64-3.69 (1H, m), 4.14-4.17 (2H,m), 6.60 (1H, s), 6.71 (1H, d, J=7.2 Hz), 7.20 (1H, d, J=8.1 Hz), 7.57(1H, d, J=4.8 Hz), 7.85 (1H, d, J=4.8 Hz), 8.41 (1H, s). [M+H] Calc'dfor C₂₂H₂₆N₂O₃, 367; Found, 367.

Preparation 36a: Methyl3-({[7-(2-methylthiophen-3-yl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

To a solution of Preparation 14c (285 mg, 0.756 mmol) in DME (15 mL) wasadded compound 2-methylthiophene-3-boronic acid (161 mg, 1.13 mmol),Pd(PPh₃)₄ (88 mg, 0.76 mmol) and Na₂CO₃ (1.2 mL, 2 N, 2.4 mmol). Themixture was stirred at reflux overnight under nitrogen. The mixture wasdiluted with EtOAc, filtered, and concentrated. The residue was purifiedby silica gel chromatography (PE:EtOAc=1:1) to give 117 mg (39%) of thetitle compound as a yellow oil. [M+H] Calc'd for C₂₂H₂₂N₂O₃S, 395;Found, 395.

Preparation 36b: Methyl3-({[(4S)-7-(2-methylthiophen-3-yl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate;and Preparation 37b: Methyl3-({[(4R)-7-(2-methylthiophen-3-yl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

Preparation 36a (117 mg) was separated by chiral HPLC (Column: ChiralcelOD, 250 mm*4.6 mm 5 um; Mobile phase: Hex:EtOH:DEA=70:30:0.2; F: 1.0mL/min; W: 230 nm; T=30° C.) gave 47 mg (31%) of Preparation 36b (8.686min) and 44 mg (29%) of Preparation 37b (10.759 min), each as a yellowoil.

Example 36:3-({[(4S)-7-(2-methylthiophen-3-yl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 91% yield from Preparation 36baccording to the general procedure for Example 1. ¹H NMR (400 MHz,DMSO-d₆): δ 1.89-1.93 (1H, m), 2.00-2.05 (1H, m), 2.46 (3H, s),3.19-3.22 (1H, m), 3.57-3.62 (1H, m), 3.76-3.80 (1H, m), 4.17-4.28 (2H,m), 6.82 (1H, s), 6.91-6.93 (1H, m), 7.07 (1H, d, J=5.2 Hz), 7.32-7.39(2H, m), 7.92-7.96 (2H, m), 8.07-8.09 (1H, m), 8.56 (1H, s). [M+H]Calc'd for C₂₁H₂₀N₂O₃S, 381; Found, 381.

Example 37:3-({[(4R)-7-(2-methylthiophen-3-yl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 95% yield from Preparation 37baccording to the general procedure for Example 1. ¹H NMR (400 MHz,DMSO-d₆): δ 1.90-1.93 (1H, m), 2.01-2.04 (1H, m), 2.46 (3H, s),3.16-3.21 (1H, m), 3.51-3.59 (1H, m), 3.72-3.77 (1H, m), 4.19-4.25 (2H,m), 6.82 (1H, s), 6.91-6.93 (1H, m), 7.07 (1H, d, J=5.2 Hz), 7.32-7.38(2H, m), 7.65 (1H, d, J=5.2 Hz), 7.88 (1H, d, J=5.2 Hz), 8.47 (1H, s).[M+H] Calc'd for C₂₁H₂₀N₂O₃S, 381; Found, 381.

Preparation 38a: Methyl3-({[7-(3-methylbut-1-yn-1-yl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylicAcid

To a suspension of Preparation 14c (50 mg, 0.13 mmol), 3-methyl-1-butyne(27 mg, 0.40 mmol), PPh₃ (17 mg, 0.065 mmol) and CuI (5 mg, 0.026 mmol)in TEA (10 mL) was added Pd₂(dba)₃ (12 mg, 0.013 mmol) at rt under N₂.The reaction was stirred at reflux overnight. The reaction wasconcentrated and purified by prep-HPLC to give 25 mg (52%) of the titlecompound as a yellow oil. [M+H] Calc'd for C₂₂H₂₄N₂O₃, 365; Found, 365.

Example 38:3-({[7-(3-methylbut-1-yn-1-yl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 83% yield from Preparation 38aaccording to the general procedure for Example 1. ¹H NMR (400 MHz,DMSO-d₆): δ 1.19-1.26 (6H, m), 1.87-1.99 (2H, m), 2.75-2.82 (1H, m),3.12-3.15 (1H, m), 3.48-3.54 (1H, m), 3.66-3.71 (1H, m), 4.15-4.21 (2H,m), 6.73 (1H, d, J=1.2 Hz), 6.84 (1H, dd, J=1.2, 8.0 Hz), 7.26 (1H, d,J=8.0 Hz), 7.57 (1H, d, J=4.4 Hz), 7.84 (1H, d, J=4.4 Hz), 8.41 (1H, s).[M+H] Calc'd for C₂₁H₂₂N₂O₃, 351; Found, 351.

Preparation 39a: Methyl3-({[(4S)-7-(2-chlorophenyl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate;and Preparation 40a: Methyl3-({[(4R)-7-(2-chlorophenyl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

To a solution of Preparation 14c (300 mg, 0.8 mmol) in DMF (10 mL) wasadded 2-chlorophenylboronic acid (186 mg, 1.2 mmol), Pd(PPh₃)₄ (92 mg,0.08 mmol) and K₂CO₃ (221 mg, 1.6 mmol). The mixture was stirred at 105°C. for 12 h under nitrogen. The mixture was filtered and concentrated,and the residue was purified by silica gel chromatography (PE:EtOAc=2:1)to give 150 mg (46%) of the racemate as colorless oil. [M+H] Calc'd forC₂₃H₂₁ClN₂O₃, 409; Found, 409.

Separation by chiral HPLC (Column: Chiralcel: IA 5 um 4.6*250 mm, Mobilephase: Hex:EtOH=70:30, F: 1.0 mL/min, W: 230 nm, T: 30° C.) gave 40 mg(27%) of Preparation 40a (8.862 min) and 45 mg (30%) of Preparation 39a(11.567 min), each as a yellow oil.

Example 39:3-({[(4S)-7-(2-chlorophenyl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 90% yield from Preparation 39aaccording to the general procedure for Example 1. ¹H NMR (400 MHz,CD₃OD): δ 1.92-1.97 (1H, m), 2.08-2.12 (1H, m), 3.18-3.21 (1H, m),3.51-3.56 (1H, m), 3.67-3.72 (1H, m), 4.14-4.23 (2H, m), 6.73 (1H, s),6.79 (1H, d, J=9.2 Hz), 7.19-7.25 (4H, m), 7.37 (1H, d, J=9.6 Hz), 7.13(1H, d, J=2.0 Hz), 8.12 (1H, d, J=4.0 Hz), 8.29 (1H, s). [M+H] Calc'dfor C₂₂H₁₉ClN₂O₃, 395; Found, 395.

Example 40:3-({[(4R)-7-(2-chlorophenyl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 81% yield from Preparation 40aaccording to the general procedure for Example 1. ¹H NMR (400 MHz,CD₃OD): δ 1.92-1.97 (1H, m), 2.08-2.12 (1H, m), 3.18-3.21 (1H, m),3.51-3.56 (1H, m), 3.67-3.72 (1H, m), 4.14-4.23 (2H, m), 6.73 (1H, s),6.79 (1H, d, J=9.2 Hz), 7.19-7.25 (4H, m), 7.37 (1H, d, J=9.6 Hz), 7.13(1H, d, J=2.0 Hz), 8.12 (1H, d, J=4.0 Hz), 8.29 (1H, s). [M+H] Calc'dfor C₂₂H₁₉ClN₂O₃, 395; Found, 395.

Preparation 41a: Methyl3-({[(4S)-7-(3-fluoro-2-methylphenyl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate,and Preparation 42a: Methyl3-({[(4R)-7-(3-fluoro-2-methylphenyl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

To a solution of Preparation 14c (400 mg, 1.06 mmol) in dioxane (10 mL)was added 3-fluoro-2-methylphenylboronic acid (245 mg, 1.59 mmol),Pd(PPh₃)₄ (123 mg, 1.06 mmol) and Na₂CO₃ (338 mg, 3.18 mmol). Themixture was stirred at 110° C. overnight under nitrogen. The mixture wasdiluted with EtOAc, filtered, and concentrated. Purification by silicagel chromatography (PE:EtOAc=1:1) gave 170 mg (39%) of the titlecompound as a yellow oil. [M+H] Calc'd for C₂₄H₂₃FN₂O₃, 407; Found, 407.

Separation by chiral HPLC (Column: Chiralcel IC, 250*4.6 mm 5 um; Mobilephase: Hex:EtOH=70:30; F: 1.0 mL/min; W: 230 nm; T=30° C.) gave 68 mg(32%) of Preparation 41a (6.921 min) and 68 mg (32%) of Preparation 42a(7.486 min), each as a yellow oil.

Example 41:3-({[(4S)-7-(3-fluoro-2-methylphenyl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 81% yield from Preparation 41aaccording to the general procedure for Example 1. ¹H NMR (300 MHz,DMSO-d₆): δ 1.91-2.05 (2H, m), 2.13 (3H, s), 3.18-3.22 (1H, m),3.55-3.60 (1H, m), 3.74-3.79 (1H, m), 4.19-4.26 (2H, m), 6.74 (1H, s),6.82-6.84 (1H, m), 7.04 (1H, d, J=8.0 Hz), 7.15 (1H, t, J=8.8 Hz),7.24-7.30 (1H, m), 7.39 (1H, d, J=8.0 Hz), 7.60 (1H, d, J=5.2 Hz), 7.87(1H, d, J=5.2 Hz), 8.46 (1H, s). [M+H] Calc'd for C₂₃H₂₁FN₂O₃, 393;Found, 393.

Example 42:3-({[(4R)-7-(3-fluoro-2-methylphenyl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 85% yield from Preparation 42aaccording to the general procedure for Example 1. ¹H NMR (300 MHz,DMSO-d₆): δ 1.94-2.13 (2H, m), 2.13 (3H, s), 3.18-3.21 (1H, m),3.54-3.60 (1H, m), 3.74-3.79 (1H, m), 4.21-4.26 (2H, m), 6.74 (1H, s),6.82-6.84 (1H, m), 7.04 (1H, d, J=7.6 Hz), 7.15 (1H, t, J=8.8 Hz),7.24-7.30 (1H, m), 7.39 (1H, d, J=8.0 Hz), 7.59 (1H, d, J=4.8 Hz), 7.86(1H, d, J=5.2 Hz), 8.46 (1H, s). [M+H] Calc'd for C₂₃H₂₁FN₂O₃, 393;Found, 393.

Preparation 43a: Tert-ButylN-{[(4R)-7-(5-fluoro-2-methylphenyl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}carbamate

To a suspension of Preparation 18d (200 mg, 0.58 mmol),5-fluoro-2-methylphenylboronic acid (135 mg, 0.88 mmol) and Na₂CO₃ (184mg, 1.74 mmol) in dioxane (10 mL) and H₂O (0.5 mL) was added Pd(PPh₃)₄(67 mg, 0.06 mmol) at rt under N₂. The reaction was stirred at 100° C.overnight. The reaction was filtered and purified by silica gelchromatography (PE:EtOAc=10:1) to give 150 mg (70%) of the titlecompound as a yellow oil. [M+H] Calc'd for C₂₂H₂₆FNO₃, 372; Found, 372.

Preparation 43b:[(4R)-7-(5-fluoro-2-methylphenyl)-3,4-dihydro-2H-1-benzopyran-4-yl]methanamine

To a solution of Preparation 43a (150 mg, 0.40 mmol) in EtOAc (5 mL) wasadded HCl/EtOAc (8 mL, 1.0 M) at rt, and the reaction was stirred for 2h. The solution was concentrated, re-dissolved in EtOAc, and washed withsat. Na₂CO₃. The organic layer was dried (Na₂SO₄) and concentrated togive the title compound as a yellow oil. [M+H] Calc'd for C₁₇H₁₈FNO,272; Found, 272.

Preparation 43c: Methyl3-({[(4R)-7-(5-fluoro-2-methylphenyl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 49% yield from Preparation 43baccording to the procedure for Preparation 4d. [M+H] Calc'd forC₂₄H₂₃FN₂O₃, 407; Found, 407.

Example 43:3-({[(4R)-7-(5-fluoro-2-methylphenyl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 89% yield from Preparation 43caccording to the procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ1.90-1.94 (1H, m), 2.01-2.05 (1H, m), 2.20 (3H, s), 3.17-3.21 (1H, m),3.53-3.59 (1H, m), 3.74-3.79 (1H, m), 4.18-4.26 (2H, m), 6.75 (1H, d,J=1.6 Hz), 6.85 (1H, dd, J=1.6, 8.0 Hz), 6.98 (1H, dd, J=2.8, 9.6 Hz),7.09 (1H, td, J=3.2, 8.8 Hz), 7.30 (1H, dd, J=5.6, 8.4 Hz), 7.39 (1H, d,J=8.0 Hz), 7.58 (1H, d, J=4.8 Hz), 7.86 (1H, d, J=3.2 Hz), 8.44 (1H, s).[M+H] Calc'd for C₂₃H₂₁FN₂O₃, 393; Found, 393.

Preparation 44a:[(4R)-7-(2-chloro-3-fluorophenyl)-3,4-dihydro-2H-1-benzopyran-4-yl]methanamine

The title compound was prepared in 78% yield from2-chloro-3-fluorophenylboronic acid and Preparation 18d according to theprocedures for Preparation 43a and 43b. [M+H] Calc'd for C₁₆H₁₅ClFNO,292; Found, 292.

Preparation 44b: Methyl3-({[(4R)-7-(2-chloro-3-fluorophenyl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 28% yield from Preparation 44aaccording to the procedure for Preparation 4d. [M+H] Calc'd forC₂₃H₂₀ClFN₂O₃, 427; Found, 427.

Example 44:3-({[(4R)-7-(2-chloro-3-fluorophenyl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 48% yield from Preparation 44baccording to the procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ1.90-1.96 (m, 1H), 2.00-2.07 (m, 1H), 3.19-3.23 (m, 1H), 3.53-3.59 (m,1H), 3.73-3.78 (m, 1H), 4.20-4.29 (m, 2H), 6.96 (s, 1H), 7.04 (d, J=8.0Hz, 1H), 7.28-7.32 (m, 1H), 7.43-7.49 (m, 2H), 7.56-7.60 (m, 2H), 7.86(d, J=5.2 Hz, 1H), 8.46 (s, 1H). [M+H] Calc'd for C₂₂H₁₈ClFN₂O₃, 413;Found, 413.

Preparation 45a:[(4R)-7-(2-chloro-5-fluorophenyl)-3,4-dihydro-2H-1-benzopyran-4-yl]methanamine

The title compound was prepared in 77% yield from2-chloro-5-fluorophenylboronic acid and Preparation 18d according to theprocedures for Preparation 43a and 43b. [M+H] Calc'd for C₁₆H₁₅ClFNO,292; Found, 292.

Preparation 45b: Methyl3-({[(4R)-7-(2-chloro-5-fluorophenyl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 46% yield from Preparation 45aaccording to the procedure for Preparation 4d. [M+H] Calc'd forC₂₃H₂₀ClFN₂O₃, 427; Found, 427.

Example 45:3-({[(4R)-7-(2-chloro-5-fluorophenyl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 52% yield from Preparation 45baccording to the procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ1.89-1.94 (m, 1H), 1.99-2.07 (m, 1H), 3.18-3.22 (m, 1H), 3.52-3.60 (m,1H), 3.74-3.79 (m, 1H), 4.18-4.28 (m, 2H), 6.85 (d, J=1.2 Hz, 1H), 6.94(dd, J=7.6 Hz, 1.2 Hz, 1H), 7.24-7.29 (m, 2H), 7.43 (d, J=7.6 Hz, 1H),7.58-7.61 (m, 2H), 7.86 (d, J=4.8 Hz, 1H), 8.46 (s, 1H). [M+H] Calc'dfor C₂₂H₁₈ClFN₂O₃, 413; Found, 413.

Preparation 46a:[(4R)-7-[2-(trifluoromethyl)phenyl]-3,4-dihydro-2H-1-benzopyran-4-yl]methanamine

The title compound was prepared in 59% yield from2-(trifluoromethyl)phenylboronic acid and Preparation 18d according tothe procedures for Preparation 43a and 43b. [M+H] Calc'd for C₁₇H₁₆F₃NO,308; Found, 292.

Preparation 46b: Methyl3-({[(4R)-7-[2-(trifluoromethyl)phenyl]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxyl

The title compound was prepared in 62% yield from Preparation 45aaccording to the procedure for Preparation 4d. [M+H] Calc'd forC₂₄H₂₁F₃N₂O₃, 443; Found, 443.

Example 46:3-({[(4R)-7-[2-(trifluoromethyl)phenyl]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 66% yield from Preparation 46baccording to the procedure for Example 1. ¹H NMR (300 MHz, DMSO-d₆): δ1.90-1.95 (1H, m), 2.01-2.05 (1H, m), 3.17-3.24 (1H, m), 3.52-3.60 (1H,m), 3.74-3.80 (1H, m), 4.20-4.26 (2H, m), 6.72 (1H, s), 6.81 (1H, d,J=7.5 Hz), 7.37-7.41 (2H, m), 7.58-7.62 (2H, m), 7.70 (1H, t, J=7.5 Hz),7.80-7.87 (2H, m), 8.46 (1H, s). [M+H] Calc'd for C₂₃H₁₉F₃N₂O₃, 429;Found, 429.

Preparation 47a: 3-(3-phenoxyphenoxy)propanenitrile

To a solution of 3-phenoxyphenol (3.0 g, 16.1 mmol) in acetonitrile(10.6 mL, 161 mmol) was added tert-BuOH (120 mg, 1.6 mmol) and K₂CO₃(225 mg, 1.6 mmol). The mixture was refluxed for 2 days. The reactionwas filtered and concentrated, and the residue was purified by HPLC toget give 2.78 g (72%) of the title compound as a colorless gum. ¹H NMR(400 MHz, CDCl₃): δ 2.80 (2H, t, J=6.0 Hz), 4.15 (2H, t, J=6.0 Hz), 6.55(1H, s), 6.64 (2H, d, J=8.0 Hz), 7.02 (2H, d, J=7.6 Hz), 7.12 (1H, t,J=7.2 Hz), 7.23 (1H, t, J=8.0 Hz) 7.35 (2H, t, J=8.0 Hz).

Preparation 47b: 7-phenoxy-3,4-dihydro-2H-1-benzopyran-4-one

To a solution of Preparation 47a (2.78 g, 11.6 mmol) in TFA (4.5 mL) wasslowly added TfOH (1.54 mL) under nitrogen at 0-5° C. The mixture wasstirred at 0-5° C. for 3 h, and then at rt for 16 h. The reaction wascooled to 0° C. and quenched with water, stirring at rt for 3 h. Thereaction was extracted with EtOAc, washed with brine, dried (Na₂SO₄),and concentrated. The residue was purified by HPLC to give 2.5 g (89%)as a yellow gum. ¹H NMR (300 MHz, DMSO-d₆): δ 2.73 (2H, t, J=6.3 Hz),4.50 (2H, t, J=6.6 Hz), 6.42 (1H, s), 6.62 (1H, d, J=8.7 Hz), 7.13 (2H,d, J=7.8 Hz), 7.26 (1H, t, J=7.2 Hz), 7.46 (2H, t, J=8.1 Hz) 7.75 (1H,d, J=8.7 Hz). [M+H] Calc'd for C₁₅H₁₂O₃, 241; Found, 241.

Preparation 47c: (7-phenoxy-2H-chromen-4-yl)methanamine

The title compound was prepared in 65% yield from Preparation 47baccording to the general procedure for Preparation 16a. ¹H NMR (400 MHz,MeOD-d₄): δ 3.89 (2H, s), 4.72 (2H, d, J=4.0 Hz), 5.86 (1H, t, J=3.6Hz), 6.35 (1H, s), 6.49 (1H, d, J=6.0 Hz), 6.94 (2H, d, J=3.6 Hz), 7.08(1H, d, J=7.6 Hz), 7.15 (1H, d, J=8.8 Hz), 7.30 (2H, t, J=8.0 Hz). [M+H]Calc'd for C₁₆H₁₅NO₂, 254; Found, 254.

Preparation 47d: (7-phenoxy-3,4-dihydro-2H-1-benzopyran-4-yl)methanamine

To a solution of Preparation 47c (1.5 g, 6.0 mmol) in MeOH (150 mL) andone drop of conc. HCl under N₂ was added 10% Pd/C (250 mg) at rt. Thesuspension was stirred for 16 h at rt under H₂. The reaction mixture wasfiltered through Celite, and the pH was adjusted to 8˜9 with sat.Na₂CO₃. The solution was dried (Na₂SO₄) and concentrated to give 1.0 g(67%) of the title compound as a yellow gum. [M+H] Calc'd for C₁₆H₁₇NO₂,256; Found, 256.

Preparation 47e: Methyl3-{[(7-phenoxy-3,4-dihydro-2H-1-benzopyran-4-yl)methyl]amino}pyridine-4-carboxylate

The title compound was prepared in 15% yield from Preparation 47daccording to the general procedure for Preparation 1e. [M+H] Calc'd forC₂₃H₂₂N₂O₄, 390; Found, 390.

Preparation 47f: Methyl3-({[(4S)-7-phenoxy-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate;and Preparation 48f: Methyl3-({[(4R)-7-phenoxy-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

Preparation 47e (120 mg) was purified by chiral HPLC (Column: ChiralcelIA, 250 mm*4.6 mm 5 um; Mobile phase: Hex:EtOH=60:40; F: 1.0 mL/min; W:230 nm; T=30° C.) to give 43 mg (36%) of Preparation 48f (7.36 min) and45 mg (38%) of Preparation 47f (10.26 min), each as a pale-yellow oil.

Example 47:3-({[(4S)-7-phenoxy-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 74% yield from Preparation 47faccording to the procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ1.84-1.88 (1H, m), 1.95-2.03 (1H, m), 3.13-3.17 (1H, m), 3.53-3.59 (1H,m), 3.72-3.77 (1H, m), 4.14-4.25 (2H, m), 6.37 (1H, s), 6.50 (1H, d,J=8.4 Hz), 6.99 (2H, d, J=8.0 Hz), 7.12-7.16 (1H, m), 7.32-7.41 (3H, m),7.94 (2H, s), 8.55 (1H, s). [M+H] Calc'd for C₂₂H₂₀N₂O₄, 377; Found,377.

Example 48:3-({[(4R)-7-phenoxy-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 77% yield from Preparation 48faccording to the procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ1.86-1.89 (1H, m), 1.97-2.01 (1H, m), 3.14-3.16 (1H, m), 3.52-3.57 (1H,m), 3.73-3.77 (1H, m), 4.13-4.25 (2H, m), 6.37 (1H, s), 6.50 (1H, d,J=8.0 Hz), 6.99 (2H, d, J=8.0 Hz), 7.12-7.15 (1H, m), 7.32-7.41 (3H, m),7.95 (2H, s), 8.56 (1H, s). [M+H] Calc'd for C₂₂H₂₀N₂O₄, 377; Found,377.

Preparation 49a:7-(thiophen-2-ylsulfanyl)-3,4-dihydro-2H-1-benzopyran-4-one

7-Bromochroman-4-one (1.5 g, 6.6 mmol), thiophene-2-thiol (0.68 mL, 7.3mmol), and potassium carbonate (1.37 g, 9.9 mmol) were combined in ACN(50 mL) in a sealed vessel, and the reaction was heated at 78° C.overnight. The reaction was cooled, filtered, and concentrated.Purification by silica gel chromatography (10-60% EtOAc/hexanes) gave1.6 g (93%) of the title compound as a yellow oil. ¹H NMR (400 MHz,DMSO-d₆): δ 2.75 (2H, t, J=6.4 Hz), 4.48 (2H, t, J=6.4 Hz), 6.59 (1H, d,J=1.8 Hz), 6.75 (1H, dd, J=8.4, 1.8 Hz), 7.13-7.17 (1H, m), 7.34 (1H,dd, J=3.6, 1.2 Hz), 8.58 (1H, dd, J=5.4, 1.2 Hz), 7.75 (1H, d, J=8.4Hz). [M+H] calc'd for C₁₃H₁₀O₂S₂, 263; found 263.

Preparation 49b: [7-(thiophen-2-ylsulfanyl)-2H-chromen-4-yl]methanamine,Hydrochloride

The title compound was prepared in 25% yield from Preparation 49aaccording to the general procedure for Preparation 3a. [M+H] calc'd forC₁₄H₁₃NOS₂, 276; found 276.

Preparation 49c:[7-(thiophen-2-ylsulfanyl)-3,4-dihydro-2H-1-benzopyran-4-yl]methanamine

The title compound was prepared in quantitative yield from Preparation49b according to the general procedure for Preparation 3e. [M+H] calc'dfor C₁₄H₁₅NOS₂, 278; found 278.

Example 49:3-({[7-(thiophen-2-ylsulfanyl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 5% yield from Preparation 49caccording to the general procedure for Example 13. ¹H NMR (400 MHz,DMSO-d₆): δ 1.86-1.98 (2H, m), 3.06-3.10 (1H, m), 3.43-3.49 (1H, m),3.61-3.67 (1H, m), 4.10-4.20 (2H, m), 6.50 (1H, d, J=1.8 Hz), 6.69 (1H,dd, J=8.0, 1.8 Hz), 7.17 (1H, dd, J=5.3, 3.6 Hz), 7.26 (1H, d, J=8.1Hz), 7.39-7.42 (1H, m), 7.57 (1H, d, J=4.4 Hz), 7.81 (1H, d, J=4.4 Hz),7.82 (1H, d, J=0.9 Hz), 8.37 (1H, s). [M+H] calc'd for C₂₀H₁₈N₂O₃S, 399;found 399.

Preparation 50a: Tert-ButylN-({7-[(2-methylphenyl)sulfanyl]-2H-chromen-4-yl}methyl)carbamate

To a suspension of Preparation 16a (1.2 g, 3.5 mmol), 2-methylthiophenol(438 mg, 3.53 mmol) and Xantphos (102 mg, 0.176 mmol) in dioxane (25 mL)and DIEA (1.2 mL, 7.0 mmol) was added Pd₂dba₃ (82 mg, 0.088 mmol) at rtunder N₂. The reaction was stirred at reflux overnight. The reaction wasfiltered and concentrated. Purification by silica gel chromatography(PE:EtOAc=5:1) gave 483 mg (36%) as an orange oil. [M+H] Calc'd forC₂₂H₂₅NO₃S, 384; Found, 384.

Preparation 50b: Tert-ButylN-({7-[(2-methylphenyl)sulfanyl]-3,4-dihydro-2H-1-benzopyran-4-yl}methyl)carbamate

To a solution of Preparation 50a (483 mg, 1.26 mmol) in MeOH (10 mL) andAcOH (2 mL) was added 10% Pd/C (150 mg) at rt. The mixture was stirredovernight with 50 psi H₂. The reaction was filtered and concentrated.The residue was dissolved in EtOAc, washed with sat. Na₂CO₃, dried(Na₂SO₄), and concentrated to give 450 mg (93%) of the title compound asa pale brown oil. [M+H] Calc'd for C₂₂H₂₇NO₃S, 386; Found, 386.

Preparation 50c:{7-[(2-methylphenyl)sulfanyl]-3,4-dihydro-2H-1-benzopyran-4-yl}methanamine

To a solution of Preparation 50b (450 mg, 1.17 mmol) in EtOAc (10 mL)was added HCl/EtOAc (10 mL, 1.0 M), and the reaction stirred at rtovernight. The solution was concentrated, and the residue was dissolvedin EtOAc, washed with sat. Na₂CO₃, dried (Na₂SO₄), and concentrated togive 320 mg (96%) of the title compound as an orange oil. [M+H] Calc'dfor C₁₇H₁₉NOS, 286; Found, 286.

Preparation 50d: Methyl3-({[(4S)-7-[(2-methylphenyl)sulfanyl]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate;and Preparation 51d: Methyl3-({[(4R)-7-[(2-methylphenyl)sulfanyl]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

The racemate (150 mg) of the title compounds was prepared in 32% yieldfrom Preparation 50c according to the general procedure for Preparation1e. [M+H] Calc'd for C₂₄H₂₄N₂O₃S, 421; Found, 421.

Separation by chiral HPLC (Column: Chiralcel: IA Sum 4.6*250 mm, Mobilephase: Hex:EtOH=50:50, F: 1.0 mL/min, W: 230 nm, T: 30° C.) gave 60 mg(40%) of Preparation 51d (7.746 min) and 62 mg (41%) of Preparation 50d(10.602 min), each as a yellow oil.

Example 50:3-({[(4S)-7-[(2-methylphenyl)sulfanyl]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 76% yield from Preparation 56daccording to the general procedure for Example 1. ¹H NMR (400 MHz,DMSO-d₆): δ 1.84-1.88 (1H, m), 1.94-1.99 (1H, m), 2.31 (3H, s),3.10-3.13 (1H, m), 3.48-3.54 (1H, m), 3.66-3.70 (1H, m), 4.12-4.22 (2H,m), 6.50 (1H, s), 6.67-6.70 (1H, m), 7.20-7.35 (5H, m), 7.57 (1H, d,J=5.2 Hz), 7.85 (1H, d, J=4.8 Hz), 8.41 (1H, s). [M+H] Calc'd forC₂₃H₂₂N₂O₃S, 407; Found, 407.

Example 51:3-({[(4R)-7-[(2-methylphenyl)sulfanyl]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 90% yield from Preparation 51daccording to the general procedure for Example 1. ¹H NMR (400 MHz,DMSO-d₆): δ 1.86-1.88 (1H, m), 1.96-1.98 (1H, m), 2.31 (3H, s),3.10-3.13 (1H, m), 3.48-3.54 (1H, m), 3.66-3.71 (1H, m), 4.14-4.19 (2H,m), 6.50 (1H, s), 6.68-6.70 (1H, m), 7.22-7.35 (5H, m), 7.58 (1H, d,J=5.2 Hz), 7.85 (1H, d, J=5.2 Hz), 8.41 (1H, s). [M+H] Calc'd forC₂₃H₂₂N₂O₃S, 407; Found, 407.

Preparation 52a: Methyl3-[({7-[(3-fluorophenyl)sulfanyl]-3,4-dihydro-2H-1-benzopyran-4-yl}methyl)amino]pyridine-4-carboxylate

To a solution of Preparation 14c (310 mg, 0.82 mmol) in THF (5 mL) wasadded 3,3′-difluorodiphenyldisulfide (105 mg, 0.41 mmol), Pd(dppf)Cl₂(34 mg, 0.041 mmol) and Zn (65 mg, 0.99 mmol). The mixture was stirredat reflux for overnight under nitrogen. The mixture was diluted withEtOAc, filtered, and concentrated. The residue was purified by silicagel chromatography (PE:EtOAc=1:1) to give 112 mg (32%) of the titlecompound as a yellow oil. [M+H] Calc'd for C₂₃H₂₁F₂O₃S, 425; Found, 425.

Preparation 52b: Methyl3-({[(4S)-7-[(3-fluorophenyl)sulfanyl]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate;and Preparation 53b: Methyl3-({[(4R)-7-[(3-fluorophenyl)sulfanyl]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

Preparation 52a (112 mg) was separated by chiral HPLC (Column: ChiralcelIA, 250 mm*4.6 mm 5 um; Mobile phase: Hex:EtOH=50:50; F: 1.0 mL/min; W:230 nm; T=30° C.) to give 44 mg (29%) of Preparation 53b (7.697 min) and43 mg (29%) of Preparation 52b (10.724 min), each as a yellow oil.

Example 52:3-({[(4S)-7-[(3-fluorophenyl)sulfanyl]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 78% yield from Preparation 52baccording to the general procedure for Example 1. ¹H NMR (400 MHz,DMSO-d₆): δ 1.90-2.01 (2H, m), 3.15-3.18 (1H, m), 3.51-3.57 (1H, m),3.69-3.74 (1H, m), 4.18-4.24 (2H, m), 6.81 (1H, s), 6.89-6.92 (1H, m),7.07-7.14 (3H, m), 7.37-7.42 (2H, m), 7.58 (1H, d, J=4.8 Hz), 7.86 (1H,d, J=4.8 Hz), 8.43 (1H, s). [M+H] Calc'd for C₂₂H₁₉FN₂O₃S, 411; Found,411.

Example 53:3-({[(4R)-7-[(3-fluorophenyl)sulfanyl]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 68% yield from Preparation 53baccording to the general procedure for Example 1. ¹H NMR (400 MHz,DMSO-d₆): δ 1.90-2.01 (2H, m), 3.15-3.18 (1H, m), 3.51-3.57 (1H, m),3.69-3.74 (1H, m), 4.18-4.24 (2H, m), 6.81 (1H, s), 6.89-6.91 (1H, m),7.07-7.14 (3H, m), 7.37-7.43 (2H, m), 7.57 (1H, d, J=4.8 Hz), 7.85 (1H,d, J=5.2 Hz), 8.42 (1H, s). [M+H] Calc'd for C₂₂H₁₉FN₂O₃S, 411; Found,411.

Preparation 54a: Methyl3-[({7-[(4-fluorophenyl)sulfanyl]-3,4-dihydro-2H-1-benzopyran-4-yl}methyl)amino]pyridine-4-carboxylate

The title compound was prepared in 53% yield from3,3′-difluorodiphenyldisulfide according to the general procedure forPreparation 52a. [M+H] Calc'd for C₂₃H₂₁F₂O₃S, 425; Found, 425.

Preparation 54b: Methyl3-({[(4S)-7-[(4-fluorophenyl)sulfanyl]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate;and Preparation 55b: Methyl3-({[(4R)-7-[(4-fluorophenyl)sulfanyl]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

Preparation 54a (179 mg) was separated by chiral HPLC (Column: ChiralcelIA, 250 mm*4.6 mm 5 um; Mobile phase: Hex:EtOH=50:50; F: 1.0 mL/min; W:230 nm; T=30° C.) to give 70 mg (41%) of Preparation 55b (9.350 min) and70 mg (41%) of Preparation 54b (16.515 min), each as a yellow oil.

Example 54:3-({[(4S)-7-[(4-fluorophenyl)sulfanyl]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 86% yield from Preparation 54baccording to the general procedure for Example 1. ¹H NMR (400 MHz,DMSO-d₆): δ 1.84-1.98 (2H, m), 3.11-3.14 (1H, m), 3.48-3.54 (1H, m),3.66-3.70 (1H, m), 4.13-4.20 (2H, m), 6.62 (1H, s), 6.75-6.78 (1H, m),7.24-7.32 (3H, m), 7.41-7.45 (2H, m), 7.59 (1H, d, J=5.2 Hz), 7.86 (1H,d, J=4.8 Hz), 8.42 (1H, s). [M+H] Calc'd for C₂₂H₁₉FN₂O₃S, 411; Found,411.

Example 55:3-({[(4R)-7-[(4-fluorophenyl)sulfanyl]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 85% yield from Preparation 55baccording to the general procedure for Example 1. ¹H NMR (400 MHz,DMSO-d₆): δ 1.84-2.00 (2H, m), 3.15-3.18 (1H, m), 3.48-3.54 (1H, m),3.66-3.70 (1H, m), 4.13-4.22 (2H, m), 6.62 (1H, s), 6.76-6.78 (1H, m),7.24-7.32 (3H, m), 7.41-7.45 (2H, m), 7.58 (1H, d, J=5.2 Hz), 7.85 (1H,d, J=5.2 Hz), 8.41 (1H, s). [M+H] Calc'd for C₂₂H₁₉FN₂O₃S, 411; Found,411

Preparation 56a:6-[(6-methylpyridin-2-yl)oxy]-1,2,3,4-tetrahydronaphthalen-1-one

A suspension of 6-hydroxy-1-tetralone (3.0 g, 18 mmol),2-fluoro-6-methylpyridine (2.06 g, 18.5 mmol) and Cs₂CO₃ (12.1 g, 37.0mmol) in DMF (150 mL) was stirred at 150° C. in a sealed vesselovernight under N₂. The reaction was poured into water (300 mL) andextracted with EtOAc (3×50 mL). Organics were dried (Na₂SO₄) andconcentrated. Purification by silica gel chromatography (PE:EA=5:1) gave1.2 g (26%) of the title compound as a red oil. [M+H] calc'd forC₁₆H₁₅NO₂, 254; found 254.

Preparation 56b:{6-[(6-methylpyridin-2-yl)oxy]-3,4-dihydronaphthalen-1-yl}methanamine,Hydrochloride

The title compound was prepared in 71% yield from Preparation 56aaccording to the general procedure for Preparation 3a. [M+H] calc'd forC₁₇H₁₈N₂O, 267; found 267.

Preparation 56c:{6-[(6-methylpyridin-2-yl)oxy]-1,2,3,4-tetrahydronaphthalen-1-yl}methanamine

The title compound was prepared in quantitative yield from Preparation56b according to the general procedure for Preparation 3e. [M+H] calc'dfor C₁₇H₂₀N₂O, 269; found 269.

Preparation 56d: methyl3-[({6-[(6-methylpyridin-2-yl)oxy]-1,2,3,4-tetrahydronaphthalen-1-yl}methyl)amino]pyridine-4-carboxylicAcid

The title compound was prepared in 66% yield from Preparation 56caccording to the procedure for Preparation 1e. [M+H] Calc'd forC₂₄H₂₅N₃O₃, 404; Found, 404.

Example 56:3-[({6-[(6-methylpyridin-2-yl)oxy]-1,2,3,4-tetrahydronaphthalen-1-yl}methyl)amino]pyridine-4-carboxylicAcid

The title compound was prepared in 42% yield from Preparation 56daccording to the general procedure for Example 1. ¹H NMR (400 MHz,MeOD-d₄): δ 1.80-1.82 (1H, m), 1.97-2.01 (3H, m), 2.45 (3H, s),2.81-2.85 (2H, m), 3.21-3.24 (1H, m), 3.51-3.66 (2H, m), 6.57 (1H, d,J=8.0 Hz), 6.86-6.88 (2H, m), 7.00 (1H, d, J=7.2 Hz), 7.34 (1H, d, J=9.2Hz), 7.68 (1H, t, J=8.0 Hz), 7.83-7.89 (2H, m), 8.21 (1H, s). [M+H]Calc'd for C₂₃H₂₃N₃O₃, 390; Found, 390.

Preparation 57a: 6-amino-1,2,3,4-tetrahydronaphthalen-1-one

The suspension of 6-amino-1,2,3,4-tetrahydronaphthalen-1-one (1.0 g, 4.4mmol), o-cresol (0.72 g, 6.7 mmol), 1-pyridin-2-ylacetone (0.12 g, 0.89mmol), Cs₂CO₃ (2.9 g, 8.9 mmol) and CuBr (70 mg, 0.44 mmol) in DMSO (10mL) was stirred at 110° C. overnight under N₂. The reaction was pouredinto water and extracted with EtOAc. Organics were dried (Na₂SO₄) andconcentrated. Purification by silica gel chromatography (PE:EtOAc=30:1to 10:1) gave 0.77 g (69%) of the title compound as a colorless oil. ¹HNMR (300 MHz, CDCl₃): δ 2.07-2.15 (m, 2H), 2.19 (s, 3H), 2.62 (t, J=6.3Hz, 2H), 2.88 (t, J=6.0 Hz, 2H), 6.66 (s, 1H), 6.77 (dd, J=8.7 Hz, 2.7Hz, 1H), 6.99 (d, J=8.1 Hz, 1H), 7.11-7.30 (m, 3H), 8.01 (d, J=8.7 Hz,1H). [M+H] Calc'd for C₁₇H₁₆O₂, 253; Found, 253.

Preparation 57b:[6-(2-methylphenoxy)-3,4-dihydronaphthalen-1-yl]methanamine,Hydrochloride

The title compound was prepared in 73% yield from Preparation 57aaccording to the general procedure for Preparation 3a. [M+H] Calc'd forC₁₈H₁₉NO, 266; Found, 266.

Preparation 57c:[6-(2-methylphenoxy)-1,2,3,4-tetrahydronaphthalen-1-yl]methanamine

The title compound was prepared in 93% yield from Preparation 57baccording to the general procedure for Preparation 3e. [M+H] Calc'd forC₁₈H₂₁NO, 268; Found, 268.

Preparation 57d: Methyl3-({[(1S)-6-(2-methylphenoxy)-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate;and Preparation 58d: Methyl3-({[(1R)-6-(2-methylphenoxy)-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

The racemate (300 mg) of the title compounds was prepared in 26% yieldfrom Preparation 72c according to the general procedure for Preparation1e. [M+H] Calc'd for C₂₅H₂₆N₂O₃, 403; Found, 403.

Separation by chiral HPLC (Column: Chiralcel: IC 5 um 4.6*250 mm, Mobilephase: Hex:EtOH=70:30, F: 1.0 mL/min, W: 230 nm, T: 30° C.) gave 108 mg(36%) of Preparation 57a (6.053 min) and 108 mg (36%) of Preparation 58a(6.873 min) as a colorless oil.

Example 57:3-({[(1S)-6-(2-methylphenoxy)-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 67% yield from Preparation 57daccording to the general procedure for Example 1. ¹H NMR (400 MHz,DMSO-d₆): δ 1.63-1.67 (m, 1H), 1.78-1.84 (m, 3H), 2.17 (s, 3H),2.63-2.73 (m, 2H), 3.06-3.09 (m, 1H), 3.42-3.47 (m, 1H), 3.55-3.59 (m,1H), 6.61 (d, J=2.0 Hz, 1H), 6.65 (dd, J=6.4 Hz, 2.4 Hz, 1H), 6.86 (d,J=8.0 Hz, 1H), 7.07-7.10 (m, 1H), 7.18-7.22 (m, 1H), 7.28-7.31 (m, 2H),7.56 (d, J=5.2 Hz, 1H), 7.83 (d, J=5.2 Hz, 1H), 8.35 (s, 1H). [M+H]Calc'd for C₂₄H₂₄N₂O₃, 389; Found, 389.

Example 58:3-({[(1R)-6-(2-methylphenoxy)-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 81% yield from Preparation 58daccording to the general procedure for Example 1. ¹H NMR (400 MHz,DMSO-d₆): δ 1.63-1.67 (m, 1H), 1.78-1.84 (m, 3H), 2.17 (s, 3H),2.63-2.73 (m, 2H), 3.06-3.09 (m, 1H), 3.42-3.47 (m, 1H), 3.55-3.59 (m,1H), 6.61 (d, J=2.0 Hz, 1H), 6.65 (dd, J=6.4 Hz, 2.4 Hz, 1H), 6.86 (d,J=8.0 Hz, 1H), 7.06-7.10 (m, 1H), 7.18-7.22 (m, 1H), 7.28-7.31 (m, 2H),7.56 (d, J=5.2 Hz, 1H), 7.83 (d, J=5.2 Hz, 1H), 8.35 (s, 1H). [M+H]Calc'd for C₂₄H₂₄N₂O₃, 389; Found, 389.

Preparation 59a: 6-propoxy-1,2,3,4-tetrahydronaphthalen-1-one

6-Hydroxy-1-tetralone (2.0 g, 12.3 mmol), bromo-propane (2.24 mL, 24.7mmol), potassium iodide (2.05 g, 12.3 mmol) and potassium carbonate(3.41 g, 24.7 mmol) were combined in ACN (50 mL) in a sealed vessel, andthe reaction was stirred at 122° C. overnight. The reaction was cooled,filtered, and concentrated. Purification by silica gel chromatography(10-50% EtOAc/hexanes) gave 2.36 g (94%) of the title compound as aclear oil. ¹H NMR (400 MHz, DMSO-d₆): δ 1.04 (3H, t, J=7.4 Hz),1.79-1.85 (2H, m), 2.09-2.14 (2H, m), 2.60 (2H, t, J=6.3 Hz), 2.88-2.93(2H, t, J=6.5 Hz), 3.97 (2H, t, J=6.5 Hz), 6.69 (1H, d, J=2.3 Hz), 6.81(1H, dd, J=8.8, 4.1 Hz), 7.99 (1H, d, J=8.7 Hz). [M+H] calc'd forC₁₃H₁₆O₂, 205; found 205.

Preparation 59b: (6-propoxy-3,4-dihydronaphthalen-1-yl)methanamine,Hydrochloride

The title compound was prepared in 54% yield from Preparation 59aaccording to the general procedure for Preparation 3a. [M+H] calc'd forC₁₄H₁₈NO, 218; found 218.

Preparation 59c:(6-propoxy-1,2,3,4-tetrahydronaphthalen-1-yl)methanamine

The title compound was prepared in quantitative yield from Preparation59b according to the general procedure for Preparation 3e. [M+H] calc'dfor C₁₄H₂₀NO, 220; found 220.

Example 59:3-{[(6-propoxy-1,2,3,4-tetrahydronaphthalen-1-yl)methyl]amino}pyridine-4-carboxylicAcid

The title compound was prepared in 26% yield from Preparation 59caccording to the general procedure for Example 13. ¹H NMR (400 MHz,DMSO-d₆): δ 0.96 (3H, t, J=7.4 Hz), 1.65-1.82 (6H, m), 2.66-2.71 (2H,m), 3.02-3.05 (1H, m), 3.38-3.55 (2H, m), 3.87 (2H, t, J=6.5 Hz),6.64-6.71 (2H, m), 7.20 (1H, d, J=8.4 Hz), 7.55 (1H, d, J=5.0 Hz), 7.70(1H, br s), 7.83 (1H, d, J=5.0 Hz), 8.35 (1H, s), 13.40 (1H, br s).[M+H] calc'd for C₂₀H₂₄N₂O₃, 341; found 341.

Preparation 60a: 6-(difluoromethoxy)-1,2,3,4-tetrahydronaphthalen-1-one

A solution of 6-hydroxy-1-tetralone (5.0 g, 30.8 mmol) in DMA (75 mL)was cooled to 0° C. Freon was bubbled into the mixture for 10 min.Cs₂CO₃ (30.1 g, 92.5 mmol) was added, and the reaction was heated at 50°C. in a sealed vessel for 2 h. The mixture poured into ice-water andextracted with EtOAc. Organics were dried and concentrated. Purificationby silica gel chromatography (PE:EtOAc=10:1 to 5:1) gave 5.1 g (78%) ofthe title compound as an off-white solid. ¹H NMR (400 MHz, CDCl₃): δ2.11-2.17 (m, 2H), 2.65 (t, J=6.4 Hz, 2H), 2.96 (t, J=6.0 Hz, 2H), 6.59(t, J=73.2 Hz, 1H), 6.97 (d, J=2.0 Hz, 1H), 7.01 (dd, J=8.4 Hz, 2.0 Hz,1H), 8.05 (d, J=8.4 Hz, 1H).

Preparation 60b:[6-(difluoromethoxy)-3,4-dihydronaphthalen-1-yl]methanamine,Hydrochloride

The title compound was prepared in 53% yield from Preparation 60aaccording to the general procedure for Preparation 3a. [M+H] calc'd forC₁₂H₁₃F₂NO, 226; found 226.

Preparation 60c:[6-(difluoromethoxy)-1,2,3,4-tetrahydronaphthalen-1-yl]methanamine

The title compound was prepared in 85% yield from Preparation 60baccording to the general procedure for Preparation 3e. [M+H] calc'd forC₁₂H₁₅F₂NO, 228; found 228.

Preparation 60d: Methyl3-({[(1S)-6-(difluoromethoxy)-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate;and Preparation 61d: Methyl3-({[(1R)-6-(difluoromethoxy)-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

The racemate of the title compounds was prepared in 25% yield fromPreparation 60c according to the general procedure for Preparation 1e.

Separation by chiral HPLC (Column: Chiralcel: IC 5 um 4.6*250 mm, Mobilephase: Hex:EtOH=70:30, F: 1.0 mL/min, W: 230 nm, T: 30° C.) gave 20%yield of Preparation 60d (6.240 min) and 16% yield of Preparation 61d(6.718 min), each as a colorless oil.

Example 60:3-({[(1S)-6-(difluoromethoxy)-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 71% yield from Preparation 60daccording to the procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ1.65-1.70 (m, 1H), 1.76-1.87 (m, 3H), 2.67-2.80 (m, 2H), 3.08-3.14 (m,1H), 3.43-3.48 (m, 1H), 3.55-3.60 (m, 1H), 6.92-6.95 (m, 2H), 7.18 (t,J=74.8 Hz, 1H), 7.36 (s, 1H), 7.56 (d, J=4.8 Hz, 1H), 7.84 (d, J=4.8 Hz,1H), 8.38 (s, 1H).

[M+H] Calc'd for C₁₈H₁₈F₂N₂O₃, 349; Found, 349.

Example 61:3-({[(1R)-6-(difluoromethoxy)-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 78% yield from Preparation 61daccording to the procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ1.64-1.71 (m, 1H), 1.74-1.88 (m, 3H), 2.67-2.80 (m, 2H), 3.09-3.12 (m,1H), 3.42-3.48 (m, 1H), 3.55-3.60 (m, 1H), 6.92-6.95 (m, 2H), 7.18 (t,J=74.4 Hz, 1H), 7.36 (s, 1H), 7.56 (d, J=4.8 Hz, 1H), 7.84 (d, J=4.8 Hz,1H), 8.38 (s, 1H).

[M+H] Calc'd for C₁₈H₁₈F₂N₂O₃, 349; Found, 349.

Preparation 62a:6-[2-(trifluoromethyl)phenoxy]-1,2,3,4-tetrahydronaphthalen-1-one

To a solution of 6-hydroxy-1-tetralone (2.5 g, 15.4 mmol) and2-iodobenzotrifluoride (25 g, 92 mmol) in DMF (50 mL) was added NaH(0.74 g, 60%, 18.5 mmol) at rt. The mixture was heated to 50° C. untilthe solid was dissolved and then cooled. To the mixture was added CuCl(1.53 g, 15.4 mmol), followed by tris(dioxa 3,6-heptyl)amine (1.65 mL,5.15 mmol). The mixture was heated at 145° C. overnight. The reactionwas diluted with water, extracted with EtOAc, washed with brine, dried(Na₂SO₄), and concentrated. Purification by silica gel chromatography(0-20% EtOAc/hexanes) gave 850 mg (18%) of the title compound as ayellow oil. ¹H NMR (400 MHz, CDCl₃): δ 2.09-2.16 (2H, m), 2.63 (2H, t,J=6.2 Hz), 2.91 (2H, t, J=6.1 Hz), 6.82 (1H, d, J=2.4 Hz), 6.86 (dd, 1H,J=8.6, 2.4 Hz), 7.05 (1H, d, J=8.2 Hz), 7.27 (1H, td, J=8.2, 0.6 Hz),7.51-7.56 (1H, m), 7.71 (1H, dd, J=7.8, 1.2 Hz), 8.07 (1H, d, J=8.2 Hz).[M+H] calc'd for C₁₇H₁₃F₃O₂, 307; found 307.

Preparation 62b:{6-[2-(trifluoromethyl)phenoxy]-3,4-dihydronaphthalen-1-yl}methanamine,Hydrochloride

The title compound was prepared in 58% yield from Preparation 62aaccording to the general procedure for Preparation 3a. [M+H] calc'd forC₁₈H₁₆F₃NO, 320; found 320.

Preparation 62c:{6-[2-(trifluoromethyl)phenoxy]-1,2,3,4-tetrahydronaphthalen-1-yl}methanamine

The title compound was prepared in quantitative yield from Preparation62b according to the general procedure for Preparation 3e. ¹H NMR (400MHz, CD₃OD): δ 1.68-1.92 (4H, m), 2.68-2.72 (2H, m), 2.82-2.96 (3H, m),6.72 (1H, d, J=2.2 Hz), 6.78 (1H, dd, J=8.3, 2.4 Hz), 6.90 (1H, d, J=8.2Hz), 7.15-7.23 (2H, m), 7.47 (1H, t, J=7.2 Hz), 7.66 (1H, d, J=7.6 Hz).[M+H] calc'd for C₁₈H₁₈F₃NO, 322; found 322.

Example 62:3-[({6-[2-(trifluoromethyl)phenoxy]-1,2,3,4-tetrahydronaphthalen-1-yl}methyl)amino]pyridine-4-carboxylicAcid

The title compound was prepared in 15% yield from Preparation 62caccording to the general procedure for Example 13. ¹H NMR (400 MHz,DMSO-d₆): δ 1.66-1.85 (4H, m), 2.67-2.79 (2H, m), 3.11-3.14 (1H, m),3.44-3.63 (2H, m), 6.80-6.82 (2H, m), 6.98 (1H, d, J=8.4), 7.29 (1H, t,J=7.6 Hz), 6.37 (1H, d, J=9.2 Hz), 7.5 (1H, d, J=5.0 Hz), 7.63 (1H, t,J=7.4 Hz), 7.70 (1H, br s), 7.76 (1H, d, J=7.8 Hz), 7.83 (1H, d, J=5.0Hz), 8.36 (1H, s), 13.34 (1H, br s). [M+H] calc'd for C₂₄H₂₁F₃N₂O₃, 443;found 443.

Preparation 63a: 6-(oxan-4-ylmethoxy)-1,2,3,4-tetrahydronaphthalen-1-one

To a suspension of 6-hydroxy-1-tetralone (2.0 g, 12.4 mmol),tetrahydropyran-4-methanol (1.7 g, 14.8 mmol) and triphenylphosphine(6.5 g, 24.7 mmol) in THF (40 mL) was added DEAD (4.3 g, 24.7 mmol) at0° C. The reaction was stirred at rt overnight. The solution wasconcentrated and purified by silica gel chromatography (PE:EtOAc=12:1)to give 3.2 g (100%) of the title compound as a yellow oil. [M+H] Calc'dfor C₁₆H₂₀O₃, 261; Found, 261.

Preparation 63b:[6-(oxan-4-ylmethoxy)-3,4-dihydronaphthalen-1-yl]methanamine,Hydrochloride

The title compound was prepared in 71% yield from Preparation 63aaccording to the general procedure for Preparation 3a. [M+H] Calc'd forC₁₇H₂₃NO₂, 274; Found, 274.

Preparation 63c:[6-(oxan-4-ylmethoxy)-1,2,3,4-tetrahydronaphthalen-1-yl]methanamine

The title compound was prepared in quantitative yield from Preparation63b according to the general procedure for Preparation 3e. [M+H] Calc'dfor C₁₇H₂₅NO₂, 276; Found, 276.

Example 63:3-({[6-(oxan-4-ylmethoxy)-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 5% yield from Preparation 63caccording to the general procedure for Example 13. ¹H NMR (300 MHz,DMSO-d₆): δ 1.28-1.33 (2H, m), 1.64-1.77 (6H, m), 1.80-1.84 (1H, m),2.67-2.70 (2H, m), 3.03-3.05 (1H, m), 3.28-3.45 (3H, m), 3.51-3.52 (1H,m), 3.77 (2H, d, J=6.3 Hz), 3.84-3.89 (2H, m), 6.65-6.71 (2H, m), 7.20(1H, d, J=8.4 Hz), 7.55 (1H, d, J=5.4 Hz), 7.82 (1H, d, J=5.4 Hz), 8.35(1H, s). [M+H] Calc'd for C₂₃H₂₈N₂O₄, 397; Found, 397.

Preparation 64a:6-(4-fluoro-2-methylphenoxy)-1,2,3,4-tetrahydronaphthalen-1-one

To a suspension of 6-bromo-1,2,3,4-tetrahydronaphthalen-1-one (2.0 g,8.9 mmol), 4-fluoro-2-methylphenol (1.7 g, 13.3 mmol),1-pyridin-2-ylacetone (240 mg, 1.8 mmol) and Cs₂CO₃ (5.8 g, 17.8 mmol)in DMSO (40 mL) was added CuBr (127 mg, 0.9 mmol) at rt under N₂. Thereaction was stirred at 100° C. overnight. The reaction was cooled,diluted with water (50 mL), and extracted with EtOAc (3×50 mL). Organicswere washed with water (3×50 mL) and brine (50 mL), dried (Na₂SO₄), andconcentrated. Purification by silica gel chromatography (PE:EtOAc=30:1)gave 2.3 g (95%) of the title compound as a colorless oil. [M+H] Calc'dfor C₁₇H₁₅FO₂, 271; Found, 271.

Preparation 64b:6-(4-fluoro-2-methylphenoxy)-3,4-dihydronaphthalene-1-carboxamide

To a solution of Preparation 64a (2.3 g, 8.4 mmol) in toluene (20 mL)was added ZnI₂ (20 mg) and TMSCN (2.2 mL, 16.8 mmol) at rt, and thesolution was stirred at 60° C. overnight. The reaction was cooled to rt.H₂SO₄ (1.0 mL) was added, followed by AcOH (12 mL), H₂SO₄ (4.3 mL), andH₂O (1.3 mL). The reaction was heated to 130° C. for 6 h. The solutionwas cooled, diluted with H₂O (50 mL), and extracted with EtOAc (3×50mL). Organics were washed with brine (50 mL), dried (Na₂SO₄), andconcentrated. Purification by silica gel chromatography (PE:THF=1:1)gave 500 mg (20%) of the title compound as a white solid. [M+H] Calc'dfor C₁₈H₁₆FNO₂, 298; Found, 298.

Preparation 64c:(1R)-6-(4-fluoro-2-methylphenoxy)-1,2,3,4-tetrahydronaphthalene-1-carboxamide

To a solution of Preparation 64b (400 mg, 1.4 mmol) in MeOH (10 mL) andTHF (10 mL) was added Ru(OAc)₂[s-binap] (5 mg) at rt. The mixture washeated at 50° C. for 2 days with 2.5 MPa H₂. The reaction wasconcentrated and the resulting solid was re-crystallized from EtOAc togive 120 mg (30%) of the title compound as a white solid. [M+H] Calc'dfor C₁₈H₁₈FNO₂, 300; Found, 300. Column: Chiralcel AS-H, Mobile phase:70:30 CO₂:MeOH (0.2DEA), ee=97%, 3.04 min.

Preparation 64d:[(1R)-6-(4-fluoro-2-methylphenoxy)-1,2,3,4-tetrahydronaphthalen-1-yl]methanamine

To a solution of Preparation 64c (150 mg, 0.50 mmol) in THF (10 mL) wasadded BH₃.THF (2.5 mL, 1.0 M, 2.5 mmol) at rt. The mixture was heated at55° C. for 6 h. The reaction was cooled, diluted with water (10 mL),basified to pH 9 with sat. Na₂CO₃, and extracted with EtOAc (3×50 mL).Organics were washed with brine (50 mL), dried (Na₂SO₄), andconcentrated to give 160 mg (quant.) of the crude title compound as ayellow oil. [M+H] Calc'd for C₁₈H₂₀FNO, 286; Found, 286.

Preparation 64e: Methyl3-({[(1R)-6-(4-fluoro-2-methylphenoxy)-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

To a suspension of Preparation 64d (0.50 mmol), methyl3-bromoisonicotinate (119 mg, 0.55 mmol), Xantphos (43 mg, 0.08 mmol)and Cs₂CO₃ (228 mg, 0.70 mmol) in toluene (15 mL) was added Pd₂dba₃ (23mg, 0.03 mmol) at rt under N₂. The reaction was stirred at 100° C. for 2h. The reaction was filtered and concentrated. Purification by silicagel chromatography (PE:EtOAc=5:1) gave 88 mg (42%) of the title compoundas a yellow oil. [M+H] Calc'd for C₂₅H₂₅FN₂O₃, 421; Found, 421.

Example 64:3-({[(1R)-6-(4-fluoro-2-methylphenoxy)-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 60% yield from Preparation 64eaccording to the procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ1.64-1.67 (1H, m), 1.77-1.83 (3H, m), 2.16 (3H, s), 2.65-2.68 (2H, m),3.05-3.09 (1H, m), 3.40-3.46 (1H, m), 3.54-3.59 (1H, m), 6.59 (1H, s),6.63 (1H, dd, J=2.8, 8.4 Hz), 6.92 (1H, dd, J=5.2, 8.8 Hz), 7.04 (1H,td, J=2.8, 8.4 Hz), 7.19 (1H, dd, J=2.8, 8.2 Hz), 7.28 (1H, d, J=8.4Hz), 7.56 (1H, d, J=5.2 Hz), 7.82 (1H, d, J=4.8 Hz), 8.34 (1H, s). [M+H]Calc'd for C₂₄H₂₃FN₂O₃, 407; Found, 407.

Preparation 65a:6-(2,4-difluorophenoxy)-1,2,3,4-tetrahydronaphthalen-1-one

The title compound was prepared in 65% yield from 2,4-difluorophenolaccording to the procedure for Preparation 64a. [M+H] Calc'd forC₁₆H₁₂F₂O₂, 275; Found, 275.

Preparation 65b:6-(2,4-difluorophenoxy)-3,4-dihydronaphthalene-1-carboxamide

The title compound was prepared in 44% yield from Preparation 65aaccording to the procedure for Preparation 64b. [M+H] Calc'd forC₁₇H₁₃F₂NO₂, 302; Found, 302.

Preparation 65c:(1R)-6-(2,4-difluorophenoxy)-1,2,3,4-tetrahydronaphthalene-1-carboxamide

The title compound was prepared in 46% yield from Preparation 65baccording to the procedure for Preparation 64c. [M+H] Calc'd forC₁₇H₁₅F₂NO₂, 304; Found, 304.

Preparation 65d:[(1R)-6-(2,4-difluorophenoxy)-1,2,3,4-tetrahydronaphthalen-1-yl]methanamine

The title compound was prepared in 89% yield from Preparation 65caccording to the procedure for Preparation 64d. [M+H] Calc'd forC₁₇H₁₇F₂NO, 290; Found, 290.

Preparation 65e: Methyl3-({[(1R)-6-(2,4-difluorophenoxy)-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 52% yield from Preparation 65daccording to the procedure for Preparation 64e. [M+H] Calc'd forC₂₄H₂₂F₂N₂O₃, 425; Found, 425.

Preparation 65:3-({[(1R)-6-(2,4-difluorophenoxy)-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 67% yield from Preparation 65eaccording to the procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ1.64-1.67 (1H, m), 1.80-1.83 (3H, m), 2.66-2.69 (2H, m), 3.06-3.09 (1H,m), 3.40-3.45 (1H, m), 3.53-3.58 (1H, m), 6.67 (1H, d, J=2.4 Hz),6.71-6.74 (1H, m), 7.11-7.13 (1H, m), 7.19-7.25 (1H, s), 7.30 (1H, d,J=8.4 Hz), 7.44-7.49 (1H, m), 7.55 (1H, d, J=5.2 Hz), 7.81 (1H, d, J=5.2Hz), 8.33 (1H, s). [M+H] Calc'd for C₂₃H₂₀F₂N₂O₃, 411; Found, 411.

Preparation 66a:6-(2-fluoro-4-methylphenoxy)-1,2,3,4-tetrahydronaphthalen-1-one

The title compound was prepared in 54% yield from2-fluoro-4-methylphenol according to the procedure for Preparation 64a.[M+H] Calc'd for C₁₇H₁₅FO₂, 271; Found, 271.

Preparation 66b:[6-(2-fluoro-4-methylphenoxy)-3,4-dihydronaphthalen-1-yl]methanamine,Hydrochloride

The title compound was prepared in 78% yield from Preparation 66aaccording to the procedure for Preparation 3a. [M+H] Calc'd forC₁₈H₁₈FNO, 284; Found, 284.

Preparation 66c:[6-(2-fluoro-4-methylphenoxy)-1,2,3,4-tetrahydronaphthalen-1-yl]methanamine

The title compound was prepared in 92% yield from Preparation 66baccording to the procedure for Preparation 3e. [M+H] Calc'd forC₁₈H₂₀FNO, 286; Found, 286.

Preparation 66d: methyl3-({[(1S)-6-(2-fluoro-4-methylphenoxy)-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate;and Preparation 66e: methyl3-({[(1R)-6-(2-fluoro-4-methylphenoxy)-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

The racemate of the title compounds was prepared in 57% yield fromPreparation 66c according to the general procedure for Preparation 1e.Separation by chiral HPLC (Column: Chiralcel: IA Sum 4.6*250 mm, Mobilephase: Hex:EtOH=70:30, F: 1.0 mL/min, W: 230 nm, T: 30° C.) gave 29%yield of Preparation 66e (6.855 min) and 29% of Preparation 66d (8.064min), each as a yellow oil. [M+H] Calc'd for C₂₅H₂₅FN₂O₃, 421; Found,421.

Example 66:3-({[(1R)-6-(2-fluoro-4-methylphenoxy)-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 83% yield from Preparation 66eaccording to the procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ1.64-1.83 (4H, m), 2.32 (3H, s), 2.65-2.69 (2H, m), 3.06-3.09 (1H, m),3.41-3.47 (1H, m), 3.54-3.59 (1H, m), 6.64 (1H, s), 6.69-6.72 (1H, m),7.03-7.06 (2H, m), 7.20 (1H, d, J=12.0 Hz), 7.29 (1H, d, J=8.4 Hz), 7.57(1H, d, J=5.2 Hz), 7.84 (1H, d, J=5.2 Hz), 8.37 (1H, s). [M+H] Calc'dfor C₂₄H₂₃FN₂O₃, 407; Found, 407.

Preparation 67a: 6-(2-chlorophenoxy)-1,2,3,4-tetrahydronaphthalen-1-one

The title compound was prepared in 64% yield from 2-chlorophenolaccording to the procedure for Preparation 64a. ¹H NMR (400 MHz, CDCl₃):δ 2.09-2.15 (m, 2H), 2.62 (t, J=6.4 Hz, 2H), 2.90 (t, J=6.0 Hz, 2H),6.71 (d, J=2.4 Hz, 1H), 6.81 (dd, J=8.4 Hz, 2.4 Hz, 1H), 7.11 (dd, J=8.4Hz, 1.2 Hz, 1H), 7.17-7.22 (m, 1H), 7.28-7.33 (m, 1H), 7.50 (dd, J=8.0Hz, 1.6 Hz, 1H), 8.02 (d, J=8.4 Hz, 1H). [M+H] Calc'd for C₁₆H₁₃ClO₂,273; Found, 273.

Preparation 67b:6-(2-chlorophenoxy)-3,4-dihydronaphthalene-1-carboxamide

The title compound was prepared in 32% yield from Preparation 67aaccording to the procedure for Preparation 64b. [M+H] Calc'd forC₁₇H₁₄ClNO₂, 300; Found, 300.

Preparation 67c:(1R)-6-(2-chlorophenoxy)-1,2,3,4-tetrahydronaphthalene-1-carboxamide

The title compound was prepared in 52% yield from Preparation 67baccording to the procedure for Preparation 64c. [M+H] Calc'd forC₁₇H₁₆ClNO₂, 302; Found, 302.

Preparation 67d:[(1R)-6-(2-chlorophenoxy)-1,2,3,4-tetrahydronaphthalen-1-yl]methanamine

The title compound was prepared in 88% yield from Preparation 67caccording to the procedure for Preparation 64d. [M+H] Calc'd forC₁₇H₁₈ClNO, 288; Found, 288.

Preparation 67e: Methyl3-({[(1R)-6-(2-chlorophenoxy)-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 31% yield from Preparation 67daccording to the procedure for Preparation 64e. [M+H] Calc'd forC₂₄H₂₃ClN₂O₃, 423; Found, 423.

Example 67:3-({[(1R)-6-(2-chlorophenoxy)-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 41% yield from Preparation 67eaccording to the procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ1.66-1.70 (m, 1H), 1.78-1.85 (m, 3H), 2.65-2.75 (m, 2H), 3.09-3.13 (m,1H), 3.41-3.49 (m, 1H), 3.56-3.61 (m, 1H), 670-6.74 (m, 2H), 7.04 (dd,J=8.4 Hz, 0.8 Hz, 1H), 7.18-7.22 (m, 1H), 7.32-7.37 (m, 2H), 7.56 (d,J=5.2 Hz, 1H), 7.59 (dd, J=8.0 Hz, 1.2 Hz, 1H), 7.83 (d, J=5.2 Hz, 1H),8.36 (s, 1H). [M+H] Calc'd for C₂₃H₂₁ClN₂O₃, 409; Found, 409.

Preparation 68a:6-[(3-methylphenyl)sulfanyl]-1,2,3,4-tetrahydronaphthalen-1-one

The suspension of 5-oxo-5,6,7,8-tetrahydronaphthalen-2-yltrifluoromethanesulfonate (1.8 g, 6.1 mmol), 3-methylbenzene-1-thiol(0.76 g, 6.1 mmol), Pd₂(dba)₃ (142 mg, 0.153 mmol), Xantphos (177 mg,0.306 mmol) and DIEA (1.58 g, 12.2 mmol) in 1,4-dioxane (60 mL) wasstirred at reflux overnight under N₂. The reaction was filtered andconcentrated. Purification by silica gel chromatography (PE:EtOAc=5:1)gave 1.8 g (100%) of the title compound as an orange oil. [M+H] Calc'dfor C₁₇H₁₆OS, 269; Found, 269.

Preparation 68b:{6-[(3-methylphenyl)sulfanyl]-3,4-dihydronaphthalen-1-yl}methanamine,Hydrochloride

The title compound was prepared in 69% yield from Preparation 68aaccording to the general procedure for Preparation 3a. [M+H] Calc'd forC₁₈H₁₉NS, 282; Found, 282.

Preparation 68c:{6-[(3-methylphenyl)sulfanyl]-1,2,3,4-tetrahydronaphthalen-1-yl}methanamine

The title compound was prepared in 92% yield from Preparation 68baccording to the general procedure for Preparation 3e. [M+H] Calc'd forC₁₈H₂₁NS, 284; Found, 284.

Preparation 68d: Methyl3-({[(1S)-6-[(3-methylphenyl)sulfanyl]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate;and Preparation 69d: methyl3-({[(1R)-6-[(3-methylphenyl)sulfanyl]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

The racemate of the title compounds was prepared in 25% yield fromPreparation 68c according to the general procedure for Preparation 1e.[M+H] Calc'd for C₂₅H₂₆N₂O₂S, 419; Found, 419.

Separation by chiral HPLC (Column: Chiralcel: IA 5 um 4.6*250 mm, Mobilephase: Hex:EtOH=50:50, F: 1.0 mL/min, W: 230 nm, T: 30° C.) gave 38%yield of Preparation 68d (6.259 min) and 37% of Preparation 69d (6.802min), each as a yellow oil.

Example 68:3-({[(1S)-6-[(3-methylphenyl)sulfanyl]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 80% yield from Preparation 68daccording to the general procedure for Example 1. ¹H NMR (300 MHz,DMSO-d₆): δ 1.65-1.85 (4H, m), 2.27 (3H, s), 2.67-2.73 (2H, m),3.10-3.12 (1H, m), 3.46-3.49 (1H, m), 3.56-3.57 (1H, m), 7.05-7.15 (5H,m), 7.22-7.27 (1H, m), 7.32-7.35 (1H, m), 7.55 (1H, d, J=5.1 Hz),7.83-7.84 (1H, m), 8.35 (1H, s). [M+H] Calc'd for C₂₄H₂₄N₂O₂S, 405;Found, 405.

Example 69:3-({[(1R)-6-[(3-methylphenyl)sulfanyl]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 83% yield from Preparation 69daccording to the general procedure for Example 1. ¹H NMR (400 MHz,DMSO-d₆): δ 1.65-1.85 (4H, m), 2.27 (3H, s), 2.67-2.71 (2H, m),3.09-3.14 (1H, m), 3.46-3.50 (1H, m), 3.56-3.57 (1H, m), 7.05-7.15 (5H,m), 7.22-7.27 (1H, m), 7.33 (1H, d, J=7.8 Hz), 7.55 (1H, d, J=4.8 Hz),7.83 (1H, d, J=4.8 Hz), 8.36 (1H, s). [M+H] Calc'd for C₂₄H₂₄N₂O₂S, 405;Found, 405.

Preparation 70a:6-[(2-methylphenyl)sulfanyl]-1,2,3,4-tetrahydronaphthalen-1-one

The title compound was prepared in 92% yield from3-methylbenzene-1-thiol according to the general procedure forPreparation 68a. [M+H] Calc'd for C₁₇H₁₆OS, 269; Found, 269.

Preparation 70b:{6-[(2-methylphenyl)sulfanyl]-3,4-dihydronaphthalen-1-yl}methanamine,Hydrochloride

The title compound was prepared in 89% yield from Preparation 68aaccording to the general procedure for Preparation 3a. [M+H] Calc'd forC₁₈H₁₉NS, 282; Found, 282.

Preparation 70c:{6-[(2-methylphenyl)sulfanyl]-1,2,3,4-tetrahydronaphthalen-1-yl}methanamine

The title compound was prepared in 88% yield from Preparation 70baccording to the general procedure for Preparation 3e. [M+H] Calc'd forC₁₈H₂₁NS, 284; Found, 284.

Preparation 70d: Methyl3-({[(1S)-6-[(2-methylphenyl)sulfanyl]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate;and Preparation 70d: Methyl3-({[(1R)-6-[(2-methylphenyl)sulfanyl]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

The racemate (550 mg) of the title compounds was prepared in 37% yieldfrom Preparation 70c according to the general procedure for Preparation1e. [M+H] Calc'd for C₂₅H₂₆N₂O₂S, 419; Found, 419.

Separation by chiral HPLC (Column: Chiralcel: IC 5 um 4.6*250 mm, Mobilephase: Hex:EtOH=70:30, F: 1.0 mL/min, W: 230 nm, T: 30° C.) 160 mg (11%)of Preparation 70d (6.645 min) and 150 mg (10%) of Preparation 71d(7.659 min), each as a yellow oil.

Example 70:3-({[(1S)-6-[(2-methylphenyl)sulfanyl]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 84% yield from Preparation 70daccording to the general procedure for Example 1. ¹H NMR (300 MHz,DMSO-d₆): δ 1.64-1.68 (1H, m), 1.77-1.84 (3H, m), 2.31 (3H, s),2.67-2.70 (2H, m), 3.08-3.12 (1H, m), 3.42-3.49 (1H, m), 3.55-3.60 (1H,m), 6.95 (1H, d, J=7.8 Hz), 7.02 (1H, s), 7.12-7.25 (3H, m), 7.29-7.33(2H, m), 7.55 (1H, d, J=5.1 Hz), 7.83 (1H, d, J=5.1 Hz), 8.35 (1H, s).[M+H] Calc'd for C₂₄H₂₄N₂O₂S, 405; Found, 405.

Example 71:3-({[(1R)-6-[(2-methylphenyl)sulfanyl]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 93% yield from Preparation 71daccording to the general procedure for Example 1. ¹H NMR (300 MHz,DMSO-d₆): δ 1.64-1.68 (1H, m), 1.77-1.84 (3H, m), 2.31 (3H, s),2.67-2.70 (2H, m), 3.08-3.12 (1H, m), 3.42-3.49 (1H, m), 3.55-3.60 (1H,m), 6.95 (1H, d, J=7.8 Hz), 7.02 (1H, s), 7.12-7.25 (3H, m), 7.29-7.33(2H, m), 7.55 (1H, d, J=5.1 Hz), 7.83 (1H, d, J=5.1 Hz), 8.35 (1H, s).[M+H] Calc'd for C₂₄H₂₄N₂O₂S, 405; Found, 405.

Preparation 72a:6-[(2-fluorophenyl)sulfanyl]-1,2,3,4-tetrahydronaphthalen-1-one

To a suspension of 5-oxo-5,6,7,8-tetrahydronaphthalen-2-yl4-methylbenzene-1-sulfonate (3.0 g, 10.2 mmol),2,2′-difluorodiphenyldisulfide (1.0 mL, 5.1 mmol) and Zn (800 mg, 12.2mmol) in THF (30 mL) was added Pd(dppf)Cl₂ (374 mg, 0.51 mmol) at rtunder N₂. The reaction was stirred at reflux overnight. The reaction wasfiltered and concentrated. Purification by silica gel chromatography(PE:EtOAc=30:1 to 10:1) gave 2.4 g (86%) of the title compound as anoff-white solid. ¹H NMR (400 MHz, CDCl₃): δ 2.07-2.13 (m, 2H), 2.62 (t,J=6.4 Hz, 2H), 2.87 (t, J=6.0 Hz, 2H), 7.01-7.03 (m, 2H), 7.17-7.21 (m,2H), 7.40-7.46 (m, 1H), 7.51 (dt, J=8.0 Hz, 1.2 Hz, 1H), 7.90 (d, J=8.8Hz, 1H). [M+H] Calc'd for C₁₆H₁₃FOS, 273; Found, 273.

Preparation 72b:{6-[(2-fluorophenyl)sulfanyl]-3,4-dihydronaphthalen-1-yl}methanamine,Hydrochloride

The title compound was prepared in 80% yield from Preparation 72aaccording to the general procedure for Preparation 3a. [M+H] Calc'd forC₁₇H₁₆FNS, 286; Found, 286.

Preparation 72c:{6-[(2-fluorophenyl)sulfanyl]-1,2,3,4-tetrahydronaphthalen-1-yl}methanamine

The title compound was prepared in 71% yield from Preparation 72baccording to the general procedure for Preparation 3e. [M+H] Calc'd forC₁₇H₁₈FNS, 288; Found, 288.

Preparation 72d: Methyl3-({[(1S)-6-[(2-fluorophenyl)sulfanyl]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate;and Preparation 73d: Methyl3-({[(1R)-6-[(2-fluorophenyl)sulfanyl]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

The racemate (410 mg) of the title compounds was prepared in 28% yieldfrom Preparation 72c according to the general procedure for Preparation1e. [M+H] Calc'd for C₂₄H₂₃FN₂O₂S, 423; Found, 423.

Separation by chiral HPLC (Column: Chiralcel: IC 5 um 4.6*250 mm, Mobilephase: Hex:EtOH=70:30, F: 1.0 mL/min, W: 230 nm, T: 30° C.) gave 115 mg(28%) of Preparation 71d (7.352 min) and 114 mg (28%) of Preparation 72d(8.388 min), each as a colorless oil.

Example 72:3-({[(1S)-6-[(2-fluorophenyl)sulfanyl]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 88% yield from Preparation 72daccording to the general procedure for Example 1. ¹H NMR (400 MHz,DMSO-d₆): δ 1.64-1.70 (m, 1H), 1.76-1.86 (m, 3H), 2.65-2.76 (m, 2H),3.09-3.15 (m, 1H), 3.44-3.49 (m, 1H), 3.57-3.61 (m, 1H), 7.06-7.09 (m,1H), 7.12 (s, 1H), 7.20-7.22 (m, 2H), 7.28-7.39 (m, 3H), 7.55 (d, J=4.8Hz, 1H), 7.83 (d, J=4.8 Hz, 1H), 8.36 (s, 1H). [M+H] Calc'd forC₂₃H₂₁FN₂O₂S, 409; Found, 409.

Example 73:3-({[(1R)-6-[(2-fluorophenyl)sulfanyl]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 50% yield from Preparation 73daccording to the general procedure for Example 1. ¹H NMR (400 MHz,DMSO-d₆): δ 1.64-1.69 (m, 1H), 1.78-1.85 (m, 3H), 2.65-2.76 (m, 2H),3.10-3.14 (m, 1H), 3.44-3.50 (m, 1H), 3.57-3.61 (m, 1H), 7.07-7.09 (m,1H), 7.12 (s, 1H), 7.18-7.24 (m, 2H), 7.28-7.41 (m, 3H), 7.55 (d, J=4.8Hz, 1H), 7.83 (d, J=4.8 Hz, 1H), 8.36 (s, 1H). [M+H] Calc'd forC₂₃H₂₁FN₂O₂S, 409; Found, 409.

Preparation 74a:6-[(3-fluorophenyl)sulfanyl]-1,2,3,4-tetrahydronaphthalen-1-one

The title compound was prepared in 76% yield from3,3′-difluorodiphenyldisulfide according to the general procedure forPreparation 72a. [M+H] Calc'd for C₁₆H₁₃FOS, 273; Found, 273.

Preparation 74b:{6-[(3-fluorophenyl)sulfanyl]-3,4-dihydronaphthalen-1-yl}methanamine,Hydrochloride

The title compound was prepared in 54% yield from Preparation 74aaccording to the general procedure for Preparation 3a. [M+H] Calc'd forC₁₇H₁₆FNS, 286; Found, 286.

Preparation 74c:{6-[(3-fluorophenyl)sulfanyl]-1,2,3,4-tetrahydronaphthalen-1-yl}methanamine

The title compound was prepared in 75% yield from Preparation 74baccording to the general procedure for Preparation 3e. [M+H] Calc'd forC₁₇H₁₈FNS, 288; Found, 288.

Preparation 74d: Methyl3-({[(1S)-6-[(3-fluorophenyl)sulfanyl]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate;and Preparation 75d: Methyl3-({[(1R)-6-[(3-fluorophenyl)sulfanyl]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

The racemate (600 mg) of the title compounds was prepared in 43% yieldfrom Preparation 74c according to the general procedure for Preparation1e. [M+H] Calc'd for C₂₄H₂₃FN₂O₂S, 423; Found, 423.

Separation by chiral HPLC (Column: Chiralcel: OD-H 5 um 4.6*250 mm,Mobile phase: Hex: EtOH:DEA=70:30:0.2, F: 1.0 mL/min, W: 230 nm, T: 30°C.) gave 80 mg (13%) of Preparation 74d (6.571 min) and 70 mg (12%) ofPreparation 75d (7.213 min), each as a yellow oil.

Example 74:3-({[(1S)-6-[(3-fluorophenyl)sulfanyl]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 64% yield from Preparation 74daccording to the general procedure for Example 1. ¹H NMR (400 MHz,DMSO-d₆): δ 1.67-1.69 (1H, m), 1.79-1.83 (3H, m), 2.68-2.75 (2H, m),3.10-3.12 (1H, m), 3.36-3.42 (1H, m), 3.53-3.58 (1H, m), 7.01-7.08 (3H,m), 7.19-7.22 (2H, m), 7.35-7.42 (2H, m), 7.57 (1H, d, J=4.4 Hz), 7.78(1H, d, J=4.8 Hz), 8.23 (1H, s). [M+H] Calc'd for C₂₃H₂₁FN₂O₂S, 409;Found, 409.

Example 75:3-({[(1R)-6-[(3-fluorophenyl)sulfanyl]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 74% yield from Preparation 75daccording to the general procedure for Example 1. ¹H NMR (400 MHz,DMSO-d₆): δ 1.67-1.69 (1H, m), 1.79-1.83 (3H, m), 2.68-2.75 (2H, m),3.10-3.12 (1H, m), 3.36-3.42 (1H, m), 3.53-3.58 (1H, m), 7.01-7.08 (3H,m), 7.19-7.22 (2H, m), 7.35-7.42 (2H, m), 7.57 (1H, d, J=4.4 Hz), 7.78(1H, d, J=4.8 Hz), 8.23 (1H, s). [M+H] Calc'd for C₂₃H₂₁FN₂O₂S, 409;Found, 409.

Preparation 76a:6-[(4-fluorophenyl)sulfanyl]-1,2,3,4-tetrahydronaphthalen-1-one

To a solution of 5-oxo-5,6,7,8-tetrahydronaphthalen-2-yl4-methylbenzene-1-sulfonate (5.0 g, 17.0 mmol) in dioxane (75 mL) wasadded 4-fluorothiophenol (2.6 g, 20.4 mmol), Pd₂(dba)₃ (392 mg, 0.43mmol), Xantphos (492 mg, 0.85 mmol) and DIEA (4.4 g, 34.0 mmol). Themixture was heated to reflux overnight under nitrogen. The mixture wasfiltered and concentrated. The residue was purified by silica gelchromatography (PE:EtOAc=20:1 to 5:1) to give 3.6 g (77%) of the titlecompound as an off-white solid. ¹H NMR (400 MHz, CDCl₃): δ 2.08-2.13 (m,2H), 2.61 (t, J=6.4 Hz, 2H), 2.85 (t, J=6.0 Hz, 2H), 6.94 (br s, 1H),6.98 (dd, J=8.4 Hz, 1.6 Hz, 1H), 7.10-7.14 (m, 2H), 7.49-7.53 (m, 2H),7.88 (d, J=8.4 Hz, 1H). [M+H] Calc'd for C₁₆H₁₃FOS, 273; Found, 273.

Preparation 76b:{6-[(4-fluorophenyl)sulfanyl]-3,4-dihydronaphthalen-1-yl}methanamine,Hydrochloride

The title compound was prepared in 69% yield from Preparation 76aaccording to the general procedure for Preparation 3a. [M+H] Calc'd forC₁₇H₁₆FNS, 286; Found, 286.

Preparation 76c:{6-[(4-fluorophenyl)sulfanyl]-1,2,3,4-tetrahydronaphthalen-1-yl}methanamine

The title compound was prepared in 97% yield from Preparation 76baccording to the general procedure for Preparation 3e. [M+H] Calc'd forC₁₇H₁₈FNS, 288; Found, 288.

Preparation 76d: Methyl3-({[(1S)-6-[(4-fluorophenyl)sulfanyl]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate;and Preparation 77d: Methyl3-({[(1R)-6-[(4-fluorophenyl)sulfanyl]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

The racemate (330 mg) of the title compounds was prepared in 20% yieldfrom Preparation 76c according to the general procedure for Preparation1e. [M+H] Calc'd for C₂₄H₂₃FN₂O₂S, 423; Found, 423.

Separation by chiral HPLC (Column: Chiralcel: IC 5 um 4.6*250 mm, Mobilephase: Hex:EtOH=70:30, F: 1.0 mL/min, W: 230 nm, T: 30° C.) gave 84 mg(25%) of Preparation 76d (6.916 min) and 91 mg (28%) of Preparation 77d(7.681 min), each as a colorless oil.

Example 76:3-({[(1S)-6-[(4-fluorophenyl)sulfanyl]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 48% yield from Preparation 76daccording to the general procedure for Example 1. ¹H NMR (400 MHz,DMSO-d₆): δ 1.65-1.68 (m, 1H), 1.78-1.83 (m, 3H), 2.64-2.75 (m, 2H),3.18-3.12 (m, 1H), 3.43-3.48 (m, 1H), 3.56-3.62 (m, 1H), 7.04-7.07 (m,1H), 7.09 (s, 1H), 7.21-7.25 (m, 2H), 7.32-7.39 (m, 3H), 7.55 (d, J=5.2Hz, 1H), 7.83 (d, J=5.2 Hz, 1H), 8.35 (s, 1H). [M+H] Calc'd forC₂₃H₂₁FN₂O₂S, 409; Found, 409.

Example 77:3-({[(1R)-6-[(4-fluorophenyl)sulfanyl]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 57% yield from Preparation 77daccording to the general procedure for Example 1. ¹H NMR (400 MHz,DMSO-d₆): δ 1.64-1.69 (m, 1H), 1.77-1.84 (m, 3H), 2.65-2.75 (m, 2H),3.07-3.12 (m, 1H), 3.42-3.48 (m, 1H), 3.56-3.60 (m, 1H), 7.04-7.06 (m,1H), 7.09 (s, 1H), 7.21-7.25 (m, 2H), 7.32-7.39 (m, 3H), 7.55 (d, J=5.2Hz, 1H), 7.83 (d, J=5.2 Hz, 1H), 8.35 (s, 1H). [M+H] Calc'd forC₂₃H₂₁FN₂O₂S, 409; Found, 409.

Preparation 78a:6-[(4-methylphenyl)sulfanyl]-1,2,3,4-tetrahydronaphthalen-1-one

The title compound was prepared in 96% yield from 4-tolyl disulfideaccording to the general procedure for Preparation 72a. [M+H] Calc'd forC₁₇H₁₆OS, 269; Found, 269.

Preparation 78b:{6-[(4-methylphenyl)sulfanyl]-3,4-dihydronaphthalen-1-yl}methanamine,Hydrochloride

The title compound was prepared in 77% yield from Preparation 76aaccording to the general procedure for Preparation 3a. [M+H] Calc'd forC₁₈H₁₉NS, 282; Found, 282.

Preparation 78c:{6-[(4-methylphenyl)sulfanyl]-1,2,3,4-tetrahydronaphthalen-1-yl}methanamine

The title compound was prepared in 68% yield from Preparation 78baccording to the general procedure for Preparation 3e. [M+H] Calc'd forC₁₈H₂₁NS, 284; Found, 284.

Preparation 78d: Methyl3-({[(1S)-6-[(4-methylphenyl)sulfanyl]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate;and Preparation 79d: Methyl3-({[(1R)-6-[(4-methylphenyl)sulfanyl]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

The racemate (200 mg) of the title compounds was prepared in 20% yieldfrom Preparation 78c according to the general procedure for Preparation1e. [M+H] Calc'd for C₂₅H₂₆N₂O₂S, 419; Found, 419.

Separation by chiral HPLC (Column: Chiralcel IC, 250 mm*4.6 mm 5 um;Mobile phase: Hex:EtOH=80:20; F: 1.0 mL/min; W: 230 nm; T=30° C.) gave66 mg (33%) of Preparation 78d (9.08 min) and 66 mg (33%) of Preparation79d (10.33 min), each as a yellow oil.

Example 78:3-({[(1S)-6-[(4-methylphenyl)sulfanyl]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 40% yield from Preparation 78daccording to the general procedure for Example 1. ¹H NMR (300 MHz,DMSO-d₆): δ 1.62-1.67 (1H, m), 1.75-1.85 (3H, m), 2.29 (3H, s),2.64-2.71 (2H, m), 3.06-3.11 (1H, m), 3.41-3.48 (1H, m), 3.54-3.60 (1H,m), 6.99-7.04 (2H, m), 7.17-7.31 (5H, m), 7.55 (1H, d, J=5.1 Hz), 7.82(1H, d, J=5.1 Hz), 8.35 (1H, s). [M+H] Calc'd for C₂₄H₂₄N₂O₂S, 405;Found, 405.

Example 79:3-({[(1R)-6-[(4-methylphenyl)sulfanyl]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 40% yield from Preparation 79daccording to the general procedure for Example 1. ¹H NMR (300 MHz,DMSO-d₆): δ 1.63-1.67 (1H, m), 1.76-1.85 (3H, m), 2.29 (3H, s),2.64-2.68 (2H, m), 3.07-3.10 (1H, m), 3.40-3.47 (1H, m), 3.53-3.59 (1H,m), 6.99-7.04 (2H, m), 7.17-7.31 (5H, m), 7.54 (1H, d, J=5.1 Hz), 7.82(1H, d, J=4.8 Hz), 8.34 (1H, s). [M+H] Calc'd for C₂₄H₂₄N₂O₂S, 405;Found, 405.

Preparation 80a: 6-bromo-1,2,3,4-tetrahydronaphthalen-1-ol

To a solution of 6-bromo-1,2,3,4-tetrahydronaphthalen-1-one (2.0 g, 8.9mmol) in EtOH (20 mL) was added NaBH₄ (1.6 g, 42.7 mmol) at rt, and thereaction was stirred for 30 min. The reaction was diluted with water (10mL) and extracted with EtOAc (3×50 mL). Organics were washed with brine(50 mL), dried (Na₂SO₄) and concentrated to give 1.9 g (94%) of thetitle compound as a brown oil. [M+H] calc'd for C₁₀H₁₁BrO₂, 227, 229;found 227, 229.

Preparation 80b: triethyl(6-bromo-1,2,3,4-tetrahydronaphthalen-1-yl)methanetricarboxylate

To a solution of Preparation 80a (1.83 g, 8.1 mmol) and triethylmethanetricarboxylate (3.76 g, 16.2 mmol) in toluene (20 mL) was added n-Bu₃P(4.0 mL, 16.2 mmol), and the solution was cooled to −50° C. under N₂.DIAD (3.2 mL, 16.2 mmol) was added dropwise, and the reaction mixturestirred for 30 min. The reaction was concentrated. Water (50 mL) and 3NNaOH (50 mL) were added, and the solution was extracted with ether.Organics were washed with 3N NaOH, water, 1N HCl, and brine. Thesolution was dried (Na₂SO₄) and concentrated. Purification by silica gelchromatography (10% EtOAc/hexanes) gave 2.84 g (79%) of the titlecompound as a white solid. [M+H] calc'd for C₂₀H₂₅BrO₆, 441, 443; found441, 443.

Preparation 80c: 2-(6-bromo-1,2,3,4-tetrahydronaphthalen-1-yl)aceticAcid

To a solution of Preparation 80b (2.84 g, 6.4 mmol) in methanol (10 mL)was added 1.5 N NaOH (50 mL) at rt, and the mixture was refluxed for 20h. The reaction mixture was concentrated. Glacial acetic acid (50 mL)was added, and the reaction was refluxed for 3 h. The reaction mixturewas concentrated and the residue was taken up in water and extractedwith ether. Organics were dried (Na₂SO₄) and concentrated to give 1.58 g(91%) of the title compound as a yellow oil. [M+H] calc'd forC₁₂H₁₃BrO₂, 269, 271; found 269, 271.

Preparation 80d: (6-bromo-1,2,3,4-tetrahydronaphthalen-1-yl)methanamine

To a solution of Preparation 80c (0.8 g, 3.0 mmol) in DCM (20 mL) wasadded oxalyl chloride (0.4 mL, 4.5 mmol) and DMF (5 drops) at rt, andthe mixture was stirred for 1 h. The solvent was removed in vacuo, andthe residue was dissolved in acetone (20 mL). A solution of NaN₃ (390mg, 6.0 mmol) in H₂O (3 mL) was added slowly at 0° C. After 10 min, themixture was diluted with water and brine, and extracted with toluene.Organics were washed with brine, dried (Na₂SO₄), and then heated toreflux for 30 min. The solution was concentrated and re-dissolved indioxane (10 mL). The solution was added dropwise to conc. HCl (20 mL) at100° C. After 20 min, the reaction mixture was concentrated. The residuewas dissolved in DCM/MeOH (1:1), basified to pH 8 with sat. Na₂CO₃,filtered, and concentrated to give the title compound as pale brown oilwhich was used for next reaction without further purification. [M+H]calc'd for C₁₁H₁₄BrN, 240, 242; found 240, 242.

Preparation 80e: Methyl3-{[(7-bromo-3,4-dihydro-2H-1-benzopyran-4-yl)methyl]amino}pyridine-4-carboxylate

The title compound was prepared in 6% yield from Preparation 80daccording to the procedure for Preparation 1e. [M+H] calc'd forC₁₈H₁₉BrN₂O₂, 375, 377; found 375, 377.

Example 80: 3-({[6-(pyridin-2-ylsulfanyl)1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylicAcid

To a suspension of Preparation 80e (72 mg, 0.19 mmol), 2,2′-dipyridyldisulfide (84 mg, 0.38 mmol) and Zn (60 mg, 0.91 mmol) in DMF (5 mL) wasadded Pd(dppf)Cl₂ (30 mg, 0.038 mmol) at rt under N₂, and the reactionwas stirred at 60° C. overnight. The reaction was diluted with EtOAc,filtered, and concentrated. The residue was purified by prep-TLC(PE:EA=2:1) to give a pale brown oil. This oil was dissolved in THF (3mL) and H₂O (1 mL). LiOH.H₂O (2 mg) was added, and the reaction wasstirred at rt for 2 h. The reaction mixture was acidified to pH=3 with1.0 N aqueous HCl solution, concentrated and purified by prep-HPLC togive 4.8 mg (6%) of the title compound as a yellow solid. ¹H NMR (400MHz, CD₃OD): δ 1.81-1.86 (m, 1H), 1.91-2.08 (m, 3H), 2.86-2.91 (m, 2H),3.35-3.38 (m, 1H), 3.65-3.73 (m, 2H), 7.19 (d, J=8.4 Hz, 1H), 7.44 (d,J=7.6 Hz, 1H), 7.49-7.55 (m, 3H), 7.98 (d, J=6.0 Hz, 1H), 8.06 (t, J=7.6Hz, 1H), 8.31 (d, J=6.0 Hz, 1H), 8.44 (s, 1H), 8.55 (d, J=5.6 Hz, 1H).[M+H] Calc'd for C₂₂H₂₁N₃O₂S, 392; Found, 392.

Preparation 81a: 6-(phenylsulfanyl)-1,2,3,4-tetrahydronaphthalen-1-one

To a solution of 5-oxo-5,6,7,8-tetrahydronaphthalen-2-yl4-methylbenzene-1-sulfonate (8.83 g, 30 mmol) and diphenyl disulphide(3.27 g, 15 mmol) in THF (20 mL) was added Zn powder (2.34 g, 36 mmol)and Pd(dppf)Cl₂ (1.22 g, 1.5 mmol) under nitrogen, and the reaction wasrefluxed overnight. The mixture was filtered and concentrated. Theresidue was purified by silica gel chromatography to give 5.93 g (77%)of the title compound as an orange solid. ¹H NMR (400 MHz, CDCl₃): δ2.06-2.12 (2H, m), 2.61 (2H, t, J=6.6 Hz), 2.85 (2H, t, J=6.0 Hz),7.01-7.04 (2H, m), 7.39-7.42 (3H, m), 7.49-7.51 (2H, m), 7.89 (1H, d,J=8.0 Hz). [M+H] Calc'd for C₁₆H₁₄OS, 255; Found, 255.

Preparation 81b: 6-(benzenesulfonyl)-1,2,3,4-tetrahydronaphthalen-1-one

To a solution of Preparation 81a (1.72 g, 6.77 mmol) in MeOH/MeCN (1:1,30 mL) was added another solution of OXONE (16.6 g, 27 mmol) in water.The mixture was stirred for 2 h at rt. The reaction was diluted withEtOAc and filtered, washed with brine, dried (Na₂SO₄), and concentratedto give 1.9 g (98%) of the title compound as colorless gum. [M+H] Calc'dfor C₁₆H₁₄O₃S, 287; Found, 287.

Preparation 81c:[6-(benzenesulfonyl)-3,4-dihydronaphthalen-1-yl]methanamine

The title compound was prepared in 31% yield from Preparation 81baccording to the procedure for Preparation 3a. [M+H] Calc'd forC₁₇H₁₇NO₂S, 300; Found, 300.

Preparation 81d:[6-(benzenesulfonyl)-1,2,3,4-tetrahydronaphthalen-1-yl]methanamine

The title compound was prepared in 91% yield from Preparation 81caccording to the procedure for Preparation 3e. [M+H] Calc'd forC₁₇H₁₉NO₂S, 302; Found, 302.

Preparation 81e: Methyl3-({[6-(benzenesulfonyl)-3,4-dihydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 43% yield from Preparation 81daccording to the procedure for Preparation 1e. [M+H] Calc'd forC₂₄H₂₄N₂O₄S, 437; Found, 437.

Preparation 81f: Methyl3-({[(1S)-6-(benzenesulfonyl)-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate;and Preparation 82f: Methyl3-({[(1R)-6-(benzenesulfonyl)-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

Preparation 81e (360 mg) was separated by chiral HPLC (Column: ChiralcelAS-H, 250 mm*4.6 mm 5 um; Mobile phase: Hex:EtOH=50:50; F: 1.0 mL/min;W: 230 nm; T=30° C.) to give 116 mg (32%) of Preparation 81e (10.39 min)and 107 mg (30%) of Preparation 82e (20.88 min), each as a yellow oil.

Example 81:3-({[(1S)-6-(benzenesulfonyl)-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 81% yield from Preparation 81faccording to the general procedure for Example 1. ¹H NMR (400 MHz,DMSO-d₆): δ 1.66-1.70 (1H, m), 1.77-1.86 (3H, m), 2.75-2.88 (2H, m),3.18-3.19 (1H, m), 3.44-3.50 (1H, m), 3.56-3.61 (1H, m), 7.55-7.71 (7H,m), 7.86 (1H, d, J=5.6 Hz), 7.94 (2H, d, J=7.2 Hz), 8.41 (1H, s). [M+H]Calc'd for C₂₃H₂₂N₂O₄S, 423; Found, 423.

Example 82:3-({[(1R)-6-(benzenesulfonyl)-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 90% yield from Preparation 82faccording to the general procedure for Example 1. ¹H NMR (400 MHz,DMSO-d₆): δ 1.66-1.70 (1H, m), 1.77-1.85 (3H, m), 2.78-2.83 (2H, m),3.18-3.21 (1H, m), 3.45-3.51 (1H, m), 3.57-3.61 (1H, m), 7.55-7.76 (7H,m), 7.89 (1H, d, J=5.2 Hz), 7.94 (2H, d, J=7.2 Hz), 8.42 (1H, s). [M+H]Calc'd for C₂₃H₂₂N₂O₄S, 423; Found, 423.

Preparation 83a:6-(4-methylbenzenesulfonyl)-1,2,3,4-tetrahydronaphthalen-1-one

The title compound was prepared in 97% yield from Preparation 78aaccording to the general procedure for Preparation 81b. [M+H] Calc'd forC₁₇H₁₆O₃S, 301; Found, 301.

Preparation 83b:[6-(4-methylbenzenesulfonyl)-3,4-dihydronaphthalen-1-yl]methanamine,Hydrochloride

The title compound was prepared in 60% yield from Preparation 83aaccording to the general procedure for Preparation 3a. [M+H] Calc'd forC₁₈H₁₉NO₂S, 314; Found, 314.

Preparation 83c:[6-(4-methylbenzenesulfonyl)-1,2,3,4-tetrahydronaphthalen-1-yl]methanamine

The title compound was prepared in 78% yield from Preparation 83baccording to the procedure for Preparation 3e. [M+H] Calc'd forC₁₈H₂₁NO₂S, 316; Found, 316.

Preparation 83d: Methyl3-({[(1S)-6-(4-methylbenzenesulfonyl)-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate;and Preparation 84d: methyl3-({[(1R)-6-(4-methylbenzenesulfonyl)-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

The racemate (226 mg) of the title compounds was prepared in 24% yieldfrom Preparation 83c according to the general procedure for Preparation1e. [M+H] Calc'd for C₂₅H₂₆N₂O₄S, 451; Found, 451.

Separation by chiral HPLC (Column: Chiralcel AS-H, 250 mm*4.6 mm 5 um;Mobile phase: MeOH:EtOH=50:50; F: 1.0 mL/min; W: 230 nm; T=30° C.) gave95 mg (42%) of Preparation 83d (9.67 min), and 86 mg (38%) ofPreparation 84d (16.75 min), each as colorless oil.

Example 83:3-({[(1S)-6-(4-methylbenzenesulfonyl)-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 56% yield from Preparation 83daccording to the general procedure for Example 1. ¹H NMR (400 MHz,DMSO-d₆): δ 1.66-1.69 (1H, m), 1.76-1.84 (3H, m), 2.35 (3H, s),2.76-2.83 (2H, m), 3.15-3.18 (1H, m), 3.35-3.48 (1H, m), 3.55-3.60 (1H,m), 7.40 (2H, d, J=8.4 Hz), 7.53-7.57 (2H, m), 7.62-7.67 (2H, m),7.81-7.84 (3H, m), 8.37 (1H, s). [M+H] Calc'd for C₂₄H₂₄N₂O₄S, 437;Found, 437.

Example 84:3-({[(1R)-6-(4-methylbenzenesulfonyl)-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 63% yield from Preparation 84daccording to the general procedure for Example 1. ¹H NMR (400 MHz,DMSO-d₆): δ 1.65-1.69 (1H, m), 1.76-1.86 (3H, m), 2.36 (3H, s),2.76-2.86 (2H, m), 3.15-3.18 (1H, m), 3.35-3.48 (1H, m), 3.55-3.60 (1H,m), 7.40 (2H, d, J=8.0 Hz), 7.53-7.57 (2H, m), 7.62-7.67 (2H, m),7.81-7.84 (3H, m), 8.37 (1H, s). [M+H] Calc'd for C₂₄H₂₄N₂O₄S, 437;Found, 437.

Preparation 85a:6-(3-methylbenzenesulfonyl)-1,2,3,4-tetrahydronaphthalen-1-one

The title compound was prepared in 84% yield from Preparation 68aaccording to the general procedure for Preparation 81b. [M+H] Calc'd forC₁₇H₁₆O₃S, 301; Found, 301.

Preparation 85b:[6-(3-methylbenzenesulfonyl)-3,4-dihydronaphthalen-1-yl]methanamine,Hydrochloride

The title compound was prepared in 95% yield from Preparation 85aaccording to the general procedure for Preparation 3a. [M+H] Calc'd forC₁₈H₁₉NO₂S, 314; Found, 314.

Preparation 85c:[6-(3-methylbenzenesulfonyl)-1,2,3,4-tetrahydronaphthalen-1-yl]methanamine

The title compound was prepared in 64% yield from Preparation 85baccording to the procedure for Preparation 3e. [M+H] Calc'd forC₁₈H₂₁NO₂S, 316; Found, 316.

Preparation 85d: Methyl3-({[(1S)-6-(3-methylbenzenesulfonyl)-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate;and Preparation 86d: Methyl3-({[(1R)-6-(3-methylbenzenesulfonyl)-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

The racemate (230 mg) of the title compounds was prepared in 16% yieldfrom Preparation 85c according to the general procedure for Preparation1e. [M+H] Calc'd for C₂₅H₂₆N₂O₄S, 451; Found, 451.

Separation by chiral HPLC (Column: Chiralcel: AS 5 um 4.6*250 mm, Mobilephase: Hex:EtOH=50:50, F: 1.0 mL/min, W: 230 nm, T: 30° C.) to give 77mg (33%) of Preparation 85d (9.653 min) and 77 mg (33%) of Preparation86d (15.046 min), each as a yellow oil.

Example 85:3-({[(1S)-6-(3-methylbenzenesulfonyl)-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 95% yield from Preparation 85daccording to the general procedure for Example 1. ¹H NMR (400 MHz,DMSO-d₆): δ 1.65-1.87 (4H, m), 2.38 (3H, s), 2.76-2.88 (2H, m),3.18-3.21 (1H, m), 3.46-3.51 (1H, m), 3.58-3.63 (1H, m), 7.49-7.58 (3H,m), 7.66-7.85 (5H, m), 7.89 (1H, d, J=5.2 Hz), 8.44 (1H, s). [M+H]Calc'd for C₂₄H₂₄N₂O₄S, 437; Found, 437.

Example 86:3-({[(1R)-6-(3-methylbenzenesulfonyl)-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 78% yield from Preparation 86daccording to the general procedure for Example 1. ¹H NMR (400 MHz,DMSO-d₆): δ 1.67-1.83 (4H, m), 2.38 (3H, s), 2.78-2.88 (2H, m),3.18-3.21 (1H, m), 3.45-3.50 (1H, m), 3.57-3.62 (1H, m), 7.49-7.57 (3H,m), 7.66-7.83 (5H, m), 7.88 (1H, d, J=5.2 Hz), 8.42 (1H, s). [M+H]Calc'd for C₂₄H₂₄N₂O₄S, 437; Found, 437.

Preparation 87a:6-(3-fluorobenzenesulfonyl)-1,2,3,4-tetrahydronaphthalen-1-one

The title compound was prepared in 40% yield from Preparation 74aaccording to the general procedure for Preparation 81b. [M+H] Calc'd forC₁₆H₁₃FO₃S, 305; Found, 305.

Preparation 87b:[6-(3-fluorobenzenesulfonyl)-3,4-dihydronaphthalen-1-yl]methanamine,Hydrochloride

The title compound was prepared in 87% yield from Preparation 87aaccording to the general procedure for Preparation 3a. [M+H] Calc'd forC₁₇H₁₆FNO₂S, 318; Found, 318.

Preparation 87c:[6-(3-fluorobenzenesulfonyl)-1,2,3,4-tetrahydronaphthalen-1-yl]methanamine

The title compound was prepared in 73% yield from Preparation 87baccording to the procedure for Preparation 3e. [M+H] Calc'd forC₁₇H₁₈FNO₂S, 320; Found, 320.

Preparation 87d: methyl3-({[6-(3-fluorobenzenesulfonyl)-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 6% yield from Preparation 87caccording to the procedure for Preparation 1e. [M+H] Calc'd forC₂₄H₂₃FN₂O₄S, 455; Found, 455.

Example 87:3-({[6-(3-fluorobenzenesulfonyl)-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 73% yield from Preparation 87daccording to the general procedure for Example 1. ¹H NMR (400 MHz,DMSO-d₆): δ 1.67-1.86 (4H, m), 2.78-2.85 (2H, m), 3.18-3.22 (1H, m),3.45-3.51 (1H, m), 3.57-3.62 (1H, m), 7.54-7.59 (2H, m), 7.65-7.87 (8H,m), 8.40 (1H, s). [M+H] Calc'd for C₂₃H₂₁FN₂O₄S, 441; Found, 441.

Preparation 88a:6-(3,6-dihydro-2H-pyran-4-yl)-1,2,3,4-tetrahydronaphthalen-1-one

To a solution of 5-oxo-5,6,7,8-tetrahydronaphthalen-2-yltrifluoromethanesulfonate (1.4 g, 4.76 mmol) in dioxane (6 mL) was added3,6-dihydro-2H-pyran-4-boronic acid pinacol ester (1.0 g, 4.76 mmol),Pd(dppf)Cl₂DCM (408 mg, 0.5 mmol) and sat. NaHCO₃ solution (2 mL). Themixture was stirred at 100° C. for 2 h under nitrogen. The mixture wascooled to rt and diluted with EtOAc, filtered, and concentrated. Theresidue was purified by silica gel chromatography (PE:EtOAc=4:1) to give930 mg (86%) of the title compound as yellow solid. ¹H NMR (400 MHz,CDCl₃): δ 2.13-2.16 (2H, m), 2.53 (2H, s), 2.65 (2H, t, J=6.4 Hz), 2.96(2H, t, J=6.0 Hz), 3.94 (2H, t, J=5.6 Hz), 4.34 (2H, s), 6.26 (1H, s),7.25 (1H, d, J=5.6 Hz), 7.33 (1H, d, J=8.4 Hz), 7.99 (1H, d, J=8.0 Hz).[M+H] Calc'd for C₁₅H₁₆O₂, 229; Found, 229.

Preparation 88b: [6-(oxan-4-yl)-3,4-dihydronaphthalen-1-yl]methanamine

The title compound was prepared in 40% yield from Preparation 88aaccording to the procedure for Preparation 3a. [M+H] Calc'd forC₁₆H₂₁NO, 244; Found, 244.

Preparation 88c:[6-(oxan-4-yl)-1,2,3,4-tetrahydronaphthalen-1-yl]methanamine

The title compound was prepared in 86% yield from Preparation 88baccording to the procedure for Preparation 3e. [M+H] Calc'd forC₁₆H₂₃NO, 246; Found, 246.

Preparation 88d: Methyl3-({[6-(oxan-4-yl)-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 17% yield from Preparation 88caccording to the procedure for Preparation 1e. [M+H] Calc'd forC₂₃H₂₈N₂O₃, 381; Found, 381.

Example 88:3-({[6-(oxan-4-yl)-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 69% yield from Preparation 88daccording to the general procedure for Example 1. ¹H NMR (400 MHz,DMSO-d₆): δ 1.61-1.68 (5H, m), 1.77-1.83 (3H, m), 2.65-2.72 (3H, m),3.04-3.07 (1H, m), 3.37-3.45 (3H, m), 3.54-3.59 (1H, m), 3.91-3.94 (2H,m), 6.96 (1H, s), 7.00 (1H, d, J=8.4 Hz), 7.24 (1H, d, J=8.0 Hz), 7.56(1H, d, J=5.2 Hz), 7.83 (1H, d, J=5.2 Hz), 8.37 (1H, s). [M+H] Calc'dfor C₂₂H₂₆N₂O₃, 367; Found, 367.

Preparation 89a:6-(2-methylpyridin-4-yl)-1,2,3,4-tetrahydronaphthalen-1-one

To a suspension of 5-oxo-5,6,7,8-tetrahydronaphthalen-2-yl4-methylbenzene-1-sulfonate (1.3 g, 4.4 mmol),2-methylpyridine-4-boronic acid pinacol ester (800 mg, 3.7 mmol), Na₂CO₃(773 mg, 7.3 mmol) and LiCl.H₂O (442 mg, 7.3 mmol) in EtOH/H₂O/toluene(4.4 mL/2.3 mL/20.0 mL) was added Pd(PPh₃)₄ (211 mg, 0.2 mmol) at rtunder N₂. The reaction was stirred at 100° C. overnight. The reactionwas filtered and concentrated. Purification by silica gel chromatography(PE:EtOAc=1:1) gave 865 mg (quantitative) of the title compound as ayellow solid. [M+H] Calc'd for C₁₆H₁₅NO, 238; Found, 238.

Preparation 89b:[6-(2-methylpyridin-4-yl)-3,4-dihydronaphthalen-1-yl]methanamine,Hydrochloride

The title compound was prepared in 44% yield from Preparation 89aaccording to the procedure for Preparation 3a. [M+H] Calc'd for C₁₇H₁₈N,251; Found, 251.

Preparation 89c:[6-(2-methylpyridin-4-yl)-1,2,3,4-tetrahydronaphthalen-1-yl]methanamine

The title compound was prepared in 98% yield from Preparation 89baccording to the procedure for Preparation 3e. [M+H] Calc'd for C₁₇H₂₀N,253; Found, 253.

Preparation 89d: Methyl3-({[6-(2-methylpyridin-4-yl)-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 5% yield from Preparation 88caccording to the procedure for Preparation 1e. [M+H] Calc'd forC₂₄H₂₅N₃O₂, 388; Found, 388.

Example 89:3-({[6-(2-methylpyridin-4-yl)-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylicAcid, Hydrochloride

The title compound was prepared in 40% yield from Preparation 89daccording to the general procedure for Example 1, and the product waspurified by prep-HPLC. ¹H NMR (400 MHz, DMSO-d₆): δ 1.75-1.92 (4H, m),2.78 (3H, s), 2.85-2.89 (2H, m), 3.25-3.29 (1H, m), 3.55-3.60 (1H, m),3.68-3.73 (1H, m), 7.59 (1H, d, J=8.0 Hz), 7.80-7.82 (2H, m), 7.95-7.97(2H, m), 8.07 (1H, brs), 8.20-8.22 (1H, m), 8.33 (1H, s), 8.54 (1H, s),8.78 (1H, d, J=6.4 Hz). [M+H] Calc'd for C₂₃H₂₃N₃O₂, 374; Found, 374.

Preparation 90a: Tert-ButylN-[(6-ethenyl-3,4-dihydronaphthalen-1-yl)methyl]carbamate

To a solution of Preparation 3b (1.0 g, 2.97 mmol) in DMSO (20 mL) wasadded potassium vinyltrifluoroborate (600 mg, 4.45 mmol), K₂CO₃ (820 mg,5.94 mmol) and Pd(dppf)Cl₂ (74 mg, 0.09 mmol). The mixture was stirredat 80° C. for 2 h under nitrogen. The mixture was poured into water andextracted with EtOAc. Organics were washed with brine, dried (Na₂SO₄),and concentrated. The residue was purified by HPLC to give 700 mg (82%)of the title compound as white solid. ¹H NMR (400 MHz, CDCl₃): δ 1.48(9H, s), 2.26-2.32 (2H, m), 2.75 (2H, t, J=8.0 Hz), 4.14 (2H, d, J=4.8Hz), 4.57 (1H, s), 5.20 (1H, d, J=11.2 Hz), 5.71 (1H, d, J=17.6 Hz),6.00-6.02 (1H, m), 6.63-6.71 (1H, m), 7.19-7.24 (2H, m). [M+H] Calc'dfor C₁₈H₂₃NO₂, 286; Found, 286.

Preparation 90b: (6-ethenyl-3,4-dihydronaphthalen-1-yl)methanamine,Hydrochloride

A mixture of Preparation 90a (700 mg, 2.45 mmol) in 6N HCl/EA solution(10 mL) was stirred overnight at rt. The reaction mixture wasconcentrated to give 400 mg (88%) of the title compound as a yellowsolid. [M+H] Calc'd for C₁₃H₁₅N, 186; Found, 186.

Preparation 90c: (6-ethyl-1,2,3,4-tetrahydronaphthalen-1-yl)methanamine

The title compound was prepared in 98% yield from Preparation 88baccording to the procedure for Preparation 3e. [M+H] Calc'd for C₁₃H₁₉N,190; Found, 190.

Preparation 90d: Methyl3-{[(6-ethyl-1,2,3,4-tetrahydronaphthalen-1-yl)methyl]amino}pyridine-4-carboxylate

The title compound was prepared in 28% yield from Preparation 90caccording to the procedure for Preparation 1e. [M+H] Calc'd forC₂₀H₂₄N₂O₂, 325; Found, 325.

Preparation 90e: Methyl3-({[(1S)-6-ethyl-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate;and Preparation 91e: Methyl3-({[(1R)-6-ethyl-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

Preparation 90d (146 mg) was separated by chiral HPLC (Column: ChiralcelOJ, 250 mm*4.6 mm Sum; Mobile phase: 70:30 CO₂:MeOH; F: 1.0 mL/min; W:230 nm; T=30° C.) to give 56 mg (38%) of Preparation 91e (2.16 min) and53 mg (36%) of Preparation 90e (2.88 min), each as a yellow gum.

Example 90:3-({[(1S)-6-ethyl-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 58% yield from Preparation 90eaccording to the general procedure for Example 1. ¹H NMR (400 MHz,DMSO-d₆): δ1.15 (3H, t, J=7.6 Hz), 1.64-1.68 (1H, m), 1.77-1.83 (3H, m),2.53-2.55 (2H, m), 2.67-2.71 (2H, m), 3.04-3.07 (1H, m), 3.39-3.44 (1H,m), 3.53-3.57 (1H, m), 6.92 (1H, s), 6.95 (1H, d, J=7.6 Hz), 7.20 (1H,d, J=8.0 Hz), 7.55 (1H, d, J=5.2 Hz), 7.82 (1H, d, J=4.0 Hz), 8.35 (1H,s). [M+H] Calc'd for C₁₉H₂₂N₂O₂, 311; Found, 311.

Example 91:3-({[(1R)-6-ethyl-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 72% yield from Preparation 91eaccording to the general procedure for Example 1. ¹H NMR (400 MHz,DMSO-d₆): δ1.15 (3H, t, J=7.6 Hz), 1.63-1.69 (1H, m), 1.77-1.87 (3H, m),2.53-2.55 (2H, m), 2.65-2.75 (2H, m), 3.04-3.07 (1H, m), 3.38-3.45 (1H,m), 3.53-3.57 (1H, m), 6.92 (1H, s), 6.95 (1H, d, J=7.2 Hz), 7.20 (1H,d, J=7.6 Hz), 7.55 (1H, d, J=5.2 Hz), 7.82 (1H, d, J=4.0 Hz), 8.36 (1H,s). [M+H] Calc'd for C₁₉H₂₂N₂O₂, 311; Found, 311.

Preparation 92a: 4-(2,3-dihydro-1-benzofuran-7-yl)but-3-enoic Acid

To a solution of (2-carboxyethyl)triphenylphosphonium bromide (617 mg,1.5 mmol) in THF (20 mL) was added NaHMDS (1.5 mL, 3.0 mmol) at −20° C.,and the reaction was stirred for 20 min.2,3-Dihydro-1-benzofuran-7-carbaldehyde (200 mg, 1.4 mmol) was added tothe reaction at −78° C., and the reaction was stirred overnight whilewarming to rt. The reaction was diluted with water (30 mL) and extractedwith EtOAc (3×30 mL). Organics were washed with brine (30 mL), dried(Na₂SO₄), and concentrated to give the crude title compound as a yellowsolid. [M+H] Calc'd for C₁₂H₁₂O₃, 205; Found, 205.

Preparation 92b: 4-(2,3-dihydro-1-benzofuran-7-yl)butanoic Acid

To a solution of Preparation 92a (6.8 mmol) in MeOH (30 mL) was added10% Pd/C (200 mg) at rt under N₂. The mixture was stirred at rtovernight with 50 psi H₂. The reaction was filtered through Celite andconcentrated to give 1.2 g (86%) of the crude title compound as a yellowoil. [M+H] Calc'd for C₁₂H₁₄O₃, 207; Found, 207.

Preparation 92c: 2H,3H,6H,7H,8H,9H-naphtho[1,2-b]furan-6-one

PPA (5 mL) was added to Preparation 92b (1.2 g, 5.8 mmol) at rt, and thereaction was stirred at 95° C. for 1.5 h. The solution was poured intowater (50 mL) at rt, extracted with EtOAc (3×50 mL), washed with brine(50 mL), dried (Na₂SO₄), and concentrated. Purification by silica gelchromatography (PE:EtOAc=15:1) gave 200 mg (18%) of the title compoundas a yellow solid.

¹H NMR (300 MHz, CDCl₃): δ 2.11-2.15 (2H, m), 2.64 (2H, t, J=6.3 Hz),2.85 (2H, t, J=6.3 Hz), 3.28 (2H, t, J=8.7 Hz), 4.65 (2H, t, J=8.7 Hz),7.15 (1H, d, J=7.8 Hz), 7.62 (1H, d, J=7.8 Hz). [M+H] Calc'd forC₁₂H₁₂O₂, 189; Found, 189.

Preparation 92d: 2H,3H,8H,9H-naphtho[1,2-b]furan-6-ylmethanamine,Hydrochloride

The title compound was prepared in 72% yield from Preparation 92caccording to the general procedure for Preparation 3a. [M+H] Calc'd forC₁₃H₁₅NO, 202; Found, 202.

Preparation 92e: 2H,3H,6H,7H,8H,9H-naphtho[1,2-b]furan-6-ylmethanamine

The title compound was prepared in quantitative yield from Preparation92d according to the general procedure for Preparation 3e. [M+H] Calc'dfor C₁₃H₁₇NO, 204; Found, 204.

Preparation 92f: Methyl3-({2H,3H,6H,7H,8H,9H-naphtho[1,2-b]furan-6-ylmethyl}amino)pyridine-4-carboxylate

The title compound was prepared in 26% yield from Preparation 92faccording to the general procedure for Preparation 1e. [M+H] Calc'd forC₂₀H₂₂N₂O₃, 339; Found, 339.

Example 92:3-({2H,3H,6H,7H,8H,9H-naphtho[1,2-b]furan-6-ylmethyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 81% yield from Preparation 92faccording to the general procedure for Example 1. ¹H NMR (400 MHz,DMSO-d₆): δ 1.65-1.84 (4H, m), 2.44-2.50 (1H, m), 2.50-2.61 (1H, m),3.05-3.14 (3H, m), 3.41-3.56 (2H, m), 4.99 (2H, t, J=8.4 Hz), 6.78 (1H,d, J=7.6 Hz), 6.99 (1H, d, J=7.6 Hz), 7.57 (1H, d, J=4.8 Hz), 7.83 (1H,d, J=5.2 Hz), 8.35 (1H, s). [M+H] Calc'd for C₁₉H₂₀N₂O₃, 325; Found,325.

Preparation 93a: (6,7-dimethyl-2H-chromen-4-yl)methanamine,Hydrochloride

The title compound was prepared in 26% yield from6,7-dimethyl-3,4-dihydro-2H-1-benzopyran-4-one according to the generalprocedure for Preparation 3a. ¹H NMR (400 MHz, DMSO-d₆): δ 1.55 (2H, brs), 1.81-1.99 (2H, m), 2.09 (6H, s), 2.54-2.60 (2H, m), 2.81-2.88 (1H,m), 3.96-4.07 (2H, m), 6.50 (1H, s), 6.90 (1H, s). [M+H] calc'd forC₁₂H₁₅NO, 190; found 190.

Preparation 93b:(6,7-dimethyl-3,4-dihydro-2H-1-benzopyran-4-yl)methanamine

The title compound was prepared in quantitative yield from Preparation93a according to the general procedure for Preparation 3e. ¹H NMR (400MHz, DMSO-d₆): δ 1.55 (2H, br s), 1.81-1.99 (2H, m), 2.09 (6H, s),2.54-2.60 (2H, m), 2.81-2.88 (1H, m), 3.96-4.07 (2H, m), 6.50 (1H, s),6.90 (1H, s). [M+H] calc'd for C₁₂H₁₇NO, 192; found 192.

Example 93:3-{[(6,7-dimethyl-3,4-dihydro-2H-1-benzopyran-4-yl)methyl]amino}pyridine-4-carboxylicAcid

The title compound was prepared in 21% yield from Preparation 93baccording to the general procedure for Example 13. ¹H NMR (400 MHz,DMSO-d₆): δ 1.81-1.99 (2H, m), 2.11 (3H, s), 2.12 (3H, s), 3.02-3.06(1H, m), 3.43-3.67 (2H, m), 4.06-4.17 (2H, m), 6.56 (1H, s), 7.04 (1H,s), 7.57 (1H, d, J=5.0 Hz), 7.69 (1H, br s), 7.85 (1H, d, J=5.0 Hz),8.42 (s, 1H), 13.38 (1H, br s). [M+H] calc'd for C₁₈H₂₀N₂O₃, 313; found313.

Preparation 94a:(6-methoxy-7-methyl-3,4-dihydronaphthalen-1-yl)methanamine,Hydrochloride

The title compound was prepared in 56% yield from6-methoxy-7-methyl-1,2,3,4-tetrahydronaphthalen-1-one according to thegeneral procedure for Preparation 3a. [M+H] calc'd for C₁₃H₁₇NO, 204;found 204.

Preparation 94b:(6-methoxy-7-methyl-1,2,3,4-tetrahydronaphthalen-1-yl)methanamine

The title compound was prepared in quantitative yield from Preparation94a according to the general procedure for Preparation 3e. ¹H NMR (400MHz, CDCl₃): δ 1.65-1.85 (6H, m), 2.17 (3H, s), 2.69-2.75 (3H, m),2.84-2.97 (2H, m), 3.79 (3H, s), 6.53 (1H, s), 6.95 (1H, s). [M+H]calc'd for C₁₃H₁₉NO, 206; found 206.

Preparation 94c: Methyl3-{[(6-methoxy-7-methyl-1,2,3,4-tetrahydronaphthalen-1-yl)methyl]amino}pyridine-4-carboxylate

The title compound was prepared in 66% yield from Preparation 94baccording to the general procedure for Preparation 4d. ¹H NMR (400 MHz,DMSO-d₆): δ 1.76-1.92 (4H, m), 2.18 (3H, s), 2.74-2.79 (2H, m),3.06-3.10 (1H, m), 3.34-3.41 (1H, m), 3.52-3.59 (1H, m), 3.80 (3H, s),3.90 (3H, s), 6.56 (1H, s), 7.00 (1H, s), 7.58 (1H, br s), 7.63 (1H, d,J=5.1 Hz), 7.90 (1H, d, J=5.1 Hz), 8.34 (1H, s). [M+H] calc'd forC₂₀H₂₄N₂O₃, 341; found 341.

Example 94:3-{[(6-methoxy-7-methyl-1,2,3,4-tetrahydronaphthalen-1-yl)methyl]amino}pyridine-4-carboxylicAcid

The title compound was prepared in 63% yield from Preparation 94caccording to the general procedure for Example 1. ¹H NMR (400 MHz,DMSO-d₆): δ 1.62-1.81 (4H, m), 2.08 (3H, s), 2.66-2.71 (2H, m),2.97-3.01 (1H, m), 3.35-3.42 (1H, m), 3.50-3.56 (1H, m), 3.73 (3H, s),6.61 (1H, s), 7.05 (1H, s), 7.57 (1H, d, J=5.0 Hz), 7.71 (1H, br s),7.83 (1H, d, J=5.0 Hz), 8.35 (1H, s). [M+H] calc'd for C₁₉H₂₂N₂O₃, 327;found 327.

Preparation 95a: 4-(3,5-dimethoxyphenyl)but-3-enoic Acid

To a solution of (2-carboxyethyl)triphenylphosphonium bromide (13.7 g,33 mmol) in dry THF (50 mL) was added NaHMDS (33 mL, 66 mmol) dropwiseat −20° C. under N₂ and the reaction stirred for 20 min. The reactionwas cooled to −78° C. and 3,5-dimethoxybenzaldehyde (5.0 g, 30 mmol) wasadded, and the reaction mixture stirred overnight while warming to rt.The reaction was quenched with water and extracted with EtOAc. Theaqueous layer was acidified to pH=2 with dilute HCl solution andextracted with EtOAc again. The combined organic layers were washed withbrine, dried (Na₂SO₄) and concentrated to give 2.54 g (38%) of the titlecompound as an orange gum. [M+H] Calc'd for C₁₂H₁₄O₄, 223; Found, 223.

Preparation 95b: 4-(3,5-dimethoxyphenyl)butanoic Acid

To a solution of Preparation 95a (2.54 g, 11.4 mmol) in MeOH (25 mL) andconc. HCl (three drops) under N₂ was added 10% Pd/C (0.5 g) at rt. Thesuspension was stirred for 3 h under 50 psi of H₂. The reaction mixturewas filtered through Celite and concentrated to give 2.27 g (88%) of thetitle compound as colorless oil. [M+H] Calc'd for C₁₂H₁₆O₄, 225; Found,225.

Preparation 95c: 6,8-dimethoxy-1,2,3,4-tetrahydronaphthalen-1-one

The mixture of Preparation 95b (2.27 g, 10 mmol) and PPA (30 g) washeated at 95° C. for 30 min. The gum was dissolved in water andextracted with EtOAc. Organics were washed with brine, dried (Na₂SO₄),and concentrated. The residue was purified by silica gel chromatographyto give 1.2 g (57%) of the title compound as tan oil. ¹H NMR (400 MHz,CD₃OD): δ 1.96 (2H, t, J=6.2 Hz), 2.51 (2H, t, J=6.4 Hz), 2.85 (2H, t,J=6.0 Hz), 3.81 (3H, s), 3.83 (3H, s), 6.38 (2H, d, J=2.4 Hz). [M+H]Calc'd for C₁₂H₁₄O₃, 207; Found, 207.

Preparation 95d: (6,8-dimethoxy-3,4-dihydronaphthalen-1-yl)methanamine,Hydrochloride

The title compound was prepared in 46% yield from Preparation 95caccording to the general procedure for Preparation 3a. [M+H] Calc'd forC₁₃H₁₇NO₂, 220; Found, 220.

Preparation 95e:(6,8-dimethoxy-1,2,3,4-tetrahydronaphthalen-1-yl)methanamine

The title compound was prepared in 87% yield from Preparation 95daccording to the general procedure for Preparation 3e. [M+H] Calc'd forC₁₃H₁₉NO₂, 222; Found, 222.

Preparation 95f: Methyl3-{[(6,8-dimethoxy-1,2,3,4-tetrahydronaphthalen-1-yl)methyl]amino}pyridine-4-carboxylate

The title compound was prepared in 38% yield from Preparation 95eaccording to the general procedure for Preparation 1e. [M+H] Calc'd forC₂₀H₂₄N₂O₄, 357; Found, 357.

Example 95:3-{[(6,8-dimethoxy-1,2,3,4-tetrahydronaphthalen-1-yl)methyl]amino}pyridine-4-carboxylicAcid

The title compound was prepared in 46% yield from Preparation 95faccording to the general procedure for Example 1. ¹H NMR (400 MHz,DMSO-d₆): δ 1.51-1.57 (1H, m), 1.63-1.67 (1H, m), 1.81-1.93 (2H, m),2.61-2.75 (2H, m), 3.14-3.24 (2H, m), 3.47 (1H, d, J=10.8 Hz), 3.70 (3H,s), 3.84 (3H, s), 6.28 (1H, d, J=2.0 Hz), 6.39 (1H, d, J=2.0 Hz), 7.55(1H, d, J=5.2 Hz), 7.81 (1H, d, J=5.2 Hz), 8.53 (1H, s). [M+H] Calc'dfor C₁₉H₂₂N₂O₄, 343; Found, 343.

Preparation 96a: 4-(4-fluoro-3-methoxyphenyl)but-3-enoic Acid

To a solution of (2-carboxyethyl)triphenylphosphonium bromide (14.8 g,35.7 mmol) in THF (40 mL) was added NaHMDS (35.8 mL, 71.5 mmol) at −20°C., and the reaction was stirred for 20 min.4-Fluoro-3-methoxybenzaldehyde (5.0 g, 32.5 mmol) was added to thereaction at −78° C., and the reaction was stirred overnight whilewarming to rt. The reaction was diluted with water (30 mL) and extractedwith EtOAc (3×30 mL). Organics were washed with brine (30 mL), dried(Na₂SO₄), and concentrated to give 6.0 g (88%) of the crude titlecompound as a yellow solid. [M+H] Calc'd for C₁₁H₁₁FO₃, 211; Found, 211.

Preparation 96b: 4-(4-fluoro-3-methoxyphenyl)butanoic Acid

To a solution of Preparation 96a (6.0 g, 28.6 mmol) in MeOH (30 mL)under N₂ was added 10% Pd/C (1.2 g), and the mixture was stirred at rtovernight under 50 psi of H₂. The reaction mixture was filtered throughCelite and concentrated to give 5.8 g (96%) of the crude title compoundas an off-white solid. [M+H] Calc'd for C₁₁H₁₃FO₃, 213; Found, 213.

Preparation 96c: 7-fluoro-6-methoxy-1,2,3,4-tetrahydronaphthalen-1-one

PPA (30 g) was added to Preparation 96b (5.8 g, 27.4 mmol) at rt, andthe reaction was stirred at 95° C. for 0.5 h. The solution was pouredinto water (50 mL) at rt, and extracted with EtOAc (3×50 mL). Organicswere washed with brine (50 mL), dried (Na₂SO₄), and concentrated.Purification by silica gel chromatography (PE:EtOAc=3:1) gave 3.1 g(58%) of the title compound as an off-white solid. ¹H NMR (400 MHz,CDCl₃): δ 2.09-2.16 (2H, m), 2.60 (2H, t, J=6.4 Hz), 2.91 (2H, t, J=6.0Hz), 3.94 (3H, s), 6.75 (1H, d, J=8.0 Hz), 7.32 (1H, d, J=11.6 Hz).[M+H] Calc'd for C₁₁H₁₁FO₂, 195; Found, 195.

Preparation 96d:(7-fluoro-6-methoxy-3,4-dihydronaphthalen-1-yl)methanamine,Hydrochloride

The title compound was prepared in 83% yield from Preparation 96caccording to the general procedure for Preparation 3a. [M+H] Calc'd forC₁₂H₁₄FNO, 208; Found, 208.

Preparation 96e:(7-fluoro-6-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)methanamine

The title compound was prepared in quantitative yield from Preparation96d according to the general procedure for Preparation 3e. [M+H] Calc'dfor C₁₂H₁₆FNO, 210; Found, 210.

Preparation 96f: Methyl3-({[(1S)-7-fluoro-6-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate,and Preparation 97f: Methyl3-({[(1R)-7-fluoro-6-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

The racemate of the title compounds was prepared in 25% yield fromPreparation 96e according to the general procedure for Preparation 1e.[M+H] Calc'd for C₁₉H₂₁FN₂O₃, 345; Found, 345.

Separation by chiral HPLC (Column: Chiralcel: IA Sum 4.6*250 mm, Mobilephase: Hex:EtOH=70:30, F: 1.0 mL/min, W: 230 nm, T: 30° C.) gave 40%yield of Preparation 96f (7.937 min) and 37% of Preparation 97f (10.383min), each as a colorless oil.

Example 96:3-({[(1S)-7-fluoro-6-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 65% yield from Preparation 96faccording to the general procedure for Example 1. ¹H NMR (400 MHz,DMSO-d₆): δ 1.63-1.84 (4H, m), 2.64-2.74 (2H, m), 3.01-3.06 (1H, m),3.38-3.44 (1H, m), 3.56-3.60 (1H, m), 3.79 (3H, s), 6.85 (1H, d, J=8.8Hz), 7.17 (1H, d, J=13.2 Hz), 7.56 (1H, d, J=5.2 Hz), 7.83 (1H, d, J=5.2Hz), 8.38 (1H, s).

[M+H] Calc'd for C₁₈H₁₉FN₂O₃, 331; Found, 331.

Example 97:3-({[(1R)-7-fluoro-6-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 64% yield from Preparation 97faccording to the general procedure for Example 1. ¹H NMR (400 MHz,DMSO-d₆): δ 1.63-1.86 (4H, m), 2.63-2.74 (2H, m), 3.01-3.04 (1H, m),3.39-3.43 (1H, m), 3.56-3.60 (1H, m), 3.79 (3H, s), 6.86 (1H, d, J=9.2Hz), 7.17 (1H, d, J=12.8 Hz), 7.55 (1H, d, J=5.2 Hz), 7.83 (1H, d, J=5.2Hz), 8.38 (1H, s).

[M+H] Calc'd for C₁₈H₁₉FN₂O₃, 331; Found, 331.

Preparation 98a: 5-bromo-6-methoxy-1,2,3,4-tetrahydronaphthalen-1-one

To a suspension of 6-methoxy-1-tetralone (2.0 g, 11.4 mmol) and NBS (2.0g, 11.4 mmol) in H₂O (30 mL) was added conc. H₂SO₄ (1.2 mL, 22.7 mmol)at rt. The reaction was stirred at 60° C. for 3 h. The mixture wasfiltered, and concentrated. Purification by prep-HPLC gave 1.2 g (41%)of the title compound as a white solid. ¹H NMR (400 MHz, CDCl₃): δ2.13-2.18 (2H, m), 2.61 (2H, t, J=6.0 Hz), 3.03 (2H, t, J=6.0 Hz), 3.97(3H, s), 6.88 (1H, d, J=8.8 Hz), 8.06 (1H, d, J=8.8 Hz). [M+H] Calc'dfor C₁₁H_(n)BrO₂, 255, 257; Found, 255, 257.

Preparation 98b: 6-methoxy-5-methyl-1,2,3,4-tetrahydronaphthalen-1-one

To a suspension of Preparation 98a (100 mg, 0.39 mmol), potassiummethyltrifluoroborate (48 mg, 0.39 mmol) and Cs₂CO₃ (381 mg, 1.2 mmol)in H₂O (2 mL) and DMF (18 mL) was added Pd(dppf)Cl₂DCM (32 mg, 0.04mmol) at rt under N₂. The reaction was stirred at 120° C. overnight. Thereaction was filtered and concentrated. Purification by silica gelchromatography (PE:EtOAc=15:1) gave 40 mg (54%) of the title compound asa white solid. [M+H] Calc'd for C₁₂H₁₄O₂, 191; Found, 191.

Preparation 98c:(6-methoxy-5-methyl-3,4-dihydronaphthalen-1-yl)methanamine,Hydrochloride

The title compound was prepared in 42% yield from Preparation 98baccording to the general procedure for Preparation 3a. [M+H] Calc'd forC₁₃H₁₇NO, 204; Found, 204.

Preparation 98d:(6-methoxy-5-methyl-1,2,3,4-tetrahydronaphthalen-1-yl)methanamine

The title compound was prepared in quantitative yield from Preparation98c according to the general procedure for Preparation 3e. [M+H] Calc'dfor C₁₃H₁₉NO, 206; Found, 206.

Preparation 98d: Methyl3-({[(1S)-6-methoxy-5-methyl-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate,and Preparation 99d: Methyl3-({[(1R)-6-methoxy-5-methyl-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

The racemate of the title compounds was prepared in 43% yield fromPreparation 99c according to the general procedure for Preparation 1e.[M+H] Calc'd for C₁₉H₂₁FN₂O₃, 345; Found, 345.

Separation by chiral HPLC (Column: Chiralcel: OJ-H Sum 4.6*250 mm,Mobile phase: CO₂:MeOH=70:30, F: 1.0 mL/min, W: 230 nm, T: 30° C.) gave40% yield of Preparation 99d (2.17 min) and 28% of Preparation 98d (3.10min), each as a yellow oil.

Example 98:3-({[(1S)-6-methoxy-5-methyl-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 63% yield from Preparation 98daccording to the general procedure for Example 1. ¹H NMR (400 MHz,DMSO-d₆): δ 1.70-1.77 (3H, m), 1.83-1.86 (1H, m), 2.03 (3H, s),2.52-2.56 (1H, m), 2.63-2.67 (1H, m), 3.03-3.06 (1H, m), 3.40-3.45 (1H,m), 3.50-3.55 (1H, m), 3.74 (3H, s), 6.78 (1H, d, J=8.4 Hz), 7.12 (1H,d, J=8.4 Hz), 7.56 (1H, d, J=4.8 Hz), 7.83 (1H, d, J=4.8 Hz), 8.36 (1H,s). [M+H] Calc'd for C₁₉H₂₂N₂O₃, 327; Found, 327.

Example 99:3-({[(1R)-6-methoxy-5-methyl-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 93% yield from Preparation 99daccording to the general procedure for Example 1. ¹H NMR (400 MHz,DMSO-d₆): δ 1.70-1.77 (3H, m), 1.83-1.86 (1H, m), 2.03 (3H, s),2.52-2.56 (1H, m), 2.63-2.67 (1H, m), 3.03-3.06 (1H, m), 3.40-3.45 (1H,m), 3.50-3.55 (1H, m), 3.74 (3H, s), 6.78 (1H, d, J=8.4 Hz), 7.12 (1H,d, J=8.4 Hz), 7.56 (1H, d, J=4.8 Hz), 7.83 (1H, d, J=4.8 Hz), 8.36 (1H,s). [M+H] Calc'd for C₁₉H₂₂N₂O₃, 327; Found, 327.

Preparation 100a: 7-(2-methylphenyl)-3,4-dihydro-2H-1-benzopyran-4-one

To a solution of 7-bromo-4-chromanone (2.0 g, 8.8 mmol) in dioxane (30mL) was added 2-methylphenylboronic acid (1.8 g, 13.2 mmol), Pd(PPh₃)₄(0.5 g, 0.44 mmol) and Na₂CO₃ (2.8 g, 26.4 mmol). The mixture wasstirred at 100° C. under nitrogen overnight. The mixture was filteredand concentrated. The residue was purified by silica gel chromatography(PE:EtOAc=10:1) to give 2.1 g (quantitative) of the title compound as anoff-white solid. ¹H NMR (300 MHz, CDCl₃): δ2.29 (s, 3H), 2.85 (t, J=6.3Hz, 2H), 4.59 (t, J=6.3 Hz, 2H), 6.94 (s, 1H), 7.00 (d, J=8.1 Hz, 1H),7.19-7.32 (m, 4H), 7.93 (d, J=8.1 Hz, 1H). [M+H] Calc'd for C₁₆H₁₄O₂,239; Found, 239.

Preparation 100b: [7-(2-methylphenyl)-2H-chromen-4-yl]methanamine,Hydrochloride

The title compound was prepared in 47% yield from Preparation 100aaccording to the general procedure for Preparation 3a. [M+H] Calc'd forC₁₇H₁₇NO, 252; Found, 252.

Preparation 100c:[7-(2-methylphenyl)-3,4-dihydro-2H-1-benzopyran-4-yl]methanamine

The title compound was prepared in quantitative yield from Preparation100b according to the general procedure for Preparation 3e. [M+H] Calc'dfor C₁₇H₁₉NO, 254; Found, 254.

Preparation 100d: Methyl3-({[(4S)-7-(2-methylphenyl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate;and Preparation 101d: Methyl3-({[(4R)-7-(2-methylphenyl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

The racemate (440 mg) of the title compounds was prepared in 25% yieldfrom Preparation 100c according to the general procedure for Preparation1e. [M+H] Calc'd for C₂₄H₂₄N₂O₃, 389; Found, 389.

Separation by chiral HPLC (Column: Chiralcel: IC 5 um 4.6*250 mm, Mobilephase: Hex:EtOH=70:30, F: 1.0 mL/min, W: 230 nm, T: 30° C.) gave 179 mg(41%) of Preparation 100d (7.49 min) and 189 mg (43%) of Preparation101d (8.82 min), each as a colorless oil.

Example 100:3-({[(4S)-7-(2-methylphenyl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 80% yield from Preparation 100daccording to the general procedure for Example 1. ¹H NMR (400 MHz,DMSO-d₆): δ 1.88-1.96 (m, 1H), 2.02-2.09 (m, 1H), 2.23 (s, 3H),3.16-3.21 (m, 1H), 3.54-3.59 (m, 1H), 3.74-3.79 (m, 1H), 4.17-4.28 (m,2H), 6.72 (d, J=1.6 Hz, 1H), 6.82 (dd, J=7.6 Hz, 1.6 Hz, 1H), 7.16-7.17(m, 1H), 7.20-7.28 (m, 3H), 7.37 (d, J=7.6 Hz, 1H), 7.58 (d, J=4.8 Hz,1H), 7.86 (d, J=4.8 Hz, 1H), 8.45 (s, 1H). [M+H] Calc'd for C₂₃H₂₂N₂O₃,375; Found, 375.

Example 101:3-({[(4R)-7-(2-methylphenyl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 74% yield from Preparation 101daccording to the general procedure for Example 1. ¹H NMR (400 MHz,DMSO-d₆): δ 1.88-1.96 (m, 1H), 2.00-2.09 (m, 1H), 2.23 (s, 3H),3.17-3.22 (m, 1H), 3.54-3.62 (m, 1H), 3.74-3.79 (m, 1H), 4.17-4.29 (m,2H), 6.72 (d, J=1.6 Hz, 1H), 6.82 (dd, J=7.6 Hz, 1.6 Hz, 1H), 7.15-7.17(m, 1H), 7.20-7.29 (m, 3H), 7.37 (d, J=7.6 Hz, 1H), 7.58 (d, J=4.8 Hz,1H), 7.86 (d, J=4.8 Hz, 1H), 8.45 (s, 1H).

[M+H] Calc'd for C₂₃H₂₂N₂O₃, 375; Found, 375.

Preparation 102a: tert-butylN-{[(4R)-7-(5-fluoro-2-methoxyphenyl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}carbamate

The title compound was prepared in 80% yield from5-fluoro-2-methoxyphenylboronic acid and Preparation 18d according tothe procedures for Preparation 43a. [M+H] Calc'd for C₂₂H₂₆FNO₄, 388;Found, 388.

Preparation 102b:[(4R)-7-(5-fluoro-2-methoxyphenyl)-3,4-dihydro-2H-1-benzopyran-4-yl]methanamine

The title compound was prepared in 78% yield from Preparation 102aaccording to the procedure for Preparation 43b. [M+H] Calc'd forC₁₇H₁₈FNO₂, 288; Found, 288.

Preparation 102c: Methyl3-({[(4R)-7-(5-fluoro-2-methoxyphenyl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 56% yield from Preparation 102baccording to the procedure for Preparation 4d. [M+H] Calc'd forC₂₄H₂₃FN₂O₄, 423; Found, 423.

Example 102:3-({[(4R)-7-(5-fluoro-2-methoxyphenyl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 90% yield from Preparation 102caccording to the procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ1.90-1.94 (1H, m), 2.00-2.04 (1H, m), 3.15-3.19 (1H, m), 3.51-3.56 (1H,m), 3.72-3.76 (4H, m), 4.19-4.25 (2H, m), 6.91 (1H, s), 6.97 (1H, d,J=8.4 Hz), 7.07-7.17 (3H, m), 7.35 (1H, d, J=7.6 Hz), 7.59 (1H, d, J=5.2Hz), 7.86 (1H, d, J=4.4 Hz), 8.44 (1H, s). [M+H] Calc'd for C₂₃H₂₁FN₂O₄,409; Found, 409.

Preparation 103a: Tert-ButylN-{[(1R)-6-[(4-cyanophenyl)(methyl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}carbamate

The title compound was prepared in 47% yield from Preparation 6d and4-cyano-N-methylaniline according to the general procedure forPreparation 6e. [M+H] calc'd for C₂₄H₂₉N₃O₂, 392; found 392.

Preparation 103b:4-{[(5R)-5-(aminomethyl)-5,6,7,8-tetrahydronaphthalen-2-yl](methyl)amino}benzonitrile

The title compound was prepared in 95% yield from Preparation 103aaccording to the procedure for Preparation 43b. [M+H] Calc'd forC₁₉H₂₁N₃, 292; Found, 292.

Preparation 103c: Methyl3-({[(1R)-6-[(4-cyanophenyl)(methyl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 68% yield from Preparation 103baccording to the procedure for Preparation 4d. [M+H] Calc'd forC₂₆H₂₆N₄O₂, 427; Found, 427.

Example 103:3-({[(1R)-6-[(4-cyanophenyl)(methyl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 48% yield from Preparation 103caccording to the procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ1.62-1.87 (4H, m), 2.69-2.75 (2H, m), 3.05-3.11 (1H, m), 3.28 (3H, s),3.45-3.51 (1H, m), 3.60-3.68 (1H, m), 6.74 (2H, d, J=8.9 Hz), 6.98-7.03(2H, m), 7.40 (1H, d, J=8.9 Hz), 7.53 (2H, d, J=8.9 Hz), 7.55 (1H, d,J=5.0 Hz), 7.72 (1H, br s), 7.84 (1H, d, J=5.0 Hz), 8.37 (1H, s), 13.37(1H, br s). [M+H] Calc'd for C₂₅H₂₄N₄O₂, 436; Found, 413.

Preparation 104a: Tert-ButylN-{[(4R)-7-[(2,4-difluorophenyl)(methyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}carbamate

The title compound was prepared in 29% yield from Preparation 18d and2,4-difluoro-N-methylaniline according to the general procedure forPreparation 6e. [M+H] calc'd for C₂₂H₂₆F₂N₂O₃, 405; found 405.

Preparation 104b:(4R)-4-(aminomethyl)-N-(2,4-difluorophenyl)-N-methyl-3,4-dihydro-2H-1-benzopyran-7-amine

The title compound was prepared in 78% yield from Preparation 104aaccording to the procedure for Preparation 43b. [M+H] Calc'd forC₁₇H₁₈F₂N₂O, 305; Found, 305.

Preparation 104c: Methyl3-({[(4R)-7-[(2,4-difluorophenyl)(methyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 70% yield from Preparation 104baccording to the procedure for Preparation 4d. [M+H] Calc'd forC₂₄H₂₁₃F₂N₃O₃, 440; Found, 440.

Example 104:3-({[(4R)-7-[(2,4-difluorophenyl)(methyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 34% yield from Preparation 104caccording to the procedure for Example 1. ¹H NMR (300 MHz, DMSO-d₆): δ1.84-1.86 (1H, m), 1.93-1.95 (1H, m), 2.99-3.03 (1H, m), 3.14 (3H, s),3.42-3.46 (1H, m), 3.58-3.62 (1H, m), 4.08-4.15 (2H, m), 6.00 (1H, d,J=2.4 Hz), 6.14 (1H, d, J=6.3 Hz), 7.07-7.16 (2H, m), 7.31-7.40 (2H, m),7.55 (1H, d, J=5.1 Hz), 7.82 (1H, d, J=4.8 Hz), 8.38 (1H, s). [M+H]Calc'd for C₂₃H₂₁F₂N₃O₃, 426; Found, 426.

Preparation 105a: Tert-ButylN-{[(4R)-7-[methyl(3-methylphenyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}carbamate

The title compound was prepared in 33% yield from Preparation 18d and3-methyl-N-methylaniline according to the general procedure forPreparation 6e. [M+H] calc'd for C₂₃H₃₀N₂O₃, 383; found 383.

Preparation 105b:(4R)-4-(aminomethyl)-N-methyl-N-(3-methylphenyl)-3,4-dihydro-2H-1-benzopyran-7-amine

The title compound was prepared in 93% yield from Preparation 105aaccording to the procedure for Preparation 43b. [M+H] Calc'd forC₁₈H₂₂N₂O, 283; Found, 283.

Preparation 105c:3-({[(4R)-7-[methyl(3-methylphenyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 77% yield from Preparation 105baccording to the procedure for Preparation 4d. [M+H] Calc'd forC₂₅H₂₇N₃O₃, 418; Found, 418.

Example 105:3-({[(4R)-7-[methyl(3-methylphenyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 39% yield from Preparation 105caccording to the procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ1.86-1.87 (1H, m), 1.96-1.98 (1H, m), 2.25 (3H, s), 3.04-3.07 (1H, m),3.18 (3H, s), 3.43-3.50 (1H, m), 3.64-3.69 (1H, m), 4.11-4.18 (2H, m),6.33 (1H, d, J=2.0 Hz), 6.46 (1H, d, J=6.0 Hz), 6.76-6.83 (3H, m),7.13-7.18 (2H, m), 7.57 (1H, d, J=5.2 Hz), 7.84 (1H, d, J=5.2 Hz), 8.40(1H, s). [M+H] Calc'd for C₂₄H₂₅N₃O₃, 404; Found, 404.

Preparation 106a: Tert-ButylN-{[(1R)-6-(pyrrolidin-1-yl)-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}carbamate

To a suspension of Preparation 6d (200 mg, 0.59 mmol), pyrrolidine (84mg, 1.18 mmol), JohnPhos (27 mg, 0.09 mmol) and t-BuONa (57 mg, 0.59mmol) in toluene (10 mL) was added Pd₂dba₃ (55 mg, 0.06 mmol) under N₂,and the reaction was refluxed for 3 h. The reaction was filtered andconcentrated. Purification by HPLC gave 144 mg (73%) of the titlecompound as a yellow oil. [M+H] Calc'd for C₂₀H₃₀N₂O₂, 331; Found, 331.

Preparation 106b:[(1R)-6-(pyrrolidin-1-yl)-1,2,3,4-tetrahydronaphthalen-1-yl]methanamine

The title compound was prepared in 95% yield from Preparation 106aaccording to the procedure for Preparation 43b. [M+H] Calc'd forC₁₅H₂₂N₂, 231; Found, 231.

Preparation 106c: Methyl3-({[(1R)-6-(pyrrolidin-1-yl)-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 19% yield from Preparation 106baccording to the procedure for Preparation 4d. [M+H] Calc'd forC₂₂H₂₇N₃O₂, 366; Found, 366.

Example 106:3-({[(1R)-6-(pyrrolidin-1-yl)-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 15% yield from Preparation 106caccording to the general procedure for Example 1. ¹H NMR (300 MHz,DMSO-d₆): δ 1.61-1.62 (1H, m), 1.74-1.78 (3H, m), 1.89-1.94 (4H, m),2.63-2.66 (2H, m), 2.95-2.97 (1H, m), 3.14-3.20 (2H, m), 3.25-3.35 (2H,m), 3.38-3.49 (2H, m), 6.23 (1H, s), 6.34 (1H, d, J=6.0 Hz), 7.07 (1H,d, J=8.7 Hz), 7.55-7.56 (1H, d, J=4.5 Hz), 7.77-7.78 (1H, d, J=4.8 Hz),8.23 (1H, s). [M+H] Calc'd for C₂₁H₂₅N₃O₂, 352; Found, 352.

Preparation 107a: Tert-ButylN-{[(4R)-7-(2-chloro-5-methoxyphenyl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}carbamate

The title compound was prepared in 68% yield from2-chloro-5-methoxyphenylboronic acid and Preparation 18d according tothe procedures for Preparation 43a. [M+H] Calc'd for C₂₂H₂₆ClNO₄, 404;Found, 404.

Preparation 107b:[(4R)-7-(2-chloro-5-methoxyphenyl)-3,4-dihydro-2H-1-benzopyran-4-yl]methanamine

The title compound was prepared in 79% yield from Preparation 107aaccording to the procedure for Preparation 43b. [M+H] Calc'd forC₁₇H₁₈ClNO₂, 304; Found, 304.

Preparation 107c: Methyl3-({[(4R)-7-(2-chloro-5-methoxyphenyl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 48% yield from Preparation 107baccording to the procedure for Preparation 4d. [M+H] Calc'd forC₂₄H₂₃ClN₂O₄, 439; Found, 439.

Example 107:3-({[(4R)-7-(2-chloro-5-methoxyphenyl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 84% yield from Preparation 107caccording to the procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ1.90-1.95 (1H, m), 2.02-2.06 (1H, m), 3.18-3.21 (1H, m), 3.53-3.59 (1H,m), 3.74-3.79 (4H, m), 4.19-4.28 (2H, m), 6.84 (1H, s), 6.90-6.97 (3H,m), 7.40-7.44 (2H, m), 7.60 (1H, d, J=5.2 Hz), 7.87 (1H, d, J=5.2 Hz),8.47 (1H, s). [M+H] Calc'd for C₂₃H₂₁ClN₂O₄, 425; Found, 425.

Preparation 108a: Tert-ButylN-{[(1R)-6-(3,4-dihydro-2H-1,4-benzoxazin-4-yl)-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}carbamate

The title compound was prepared in 58% yield from Preparation 6d and3,4-dihydro-2H-1,4-benzoxazine according to the general procedure forPreparation 9a. [M+H] Calc'd for C₂₄H₃₀N₂O₃, 395; Found, 395.

Preparation 108b:[(1R)-6-(3,4-dihydro-2H-1,4-benzoxazin-4-yl)-1,2,3,4-tetrahydronaphthalen-1-yl]methanamine

The title compound was prepared in 93% yield from Preparation 108aaccording to the procedure for Preparation 43b. [M+H] Calc'd forC₁₉H₂₂N₂O, 295; Found, 295.

Preparation 108c: Methyl3-({[(1R)-6-(3,4-dihydro-2H-1,4-benzoxazin-4-yl)-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 55% yield from Preparation 108baccording to the procedure for Preparation 4d. [M+H] Calc'd forC₂₆H₂₇N₃O₃, 430; Found, 430.

Example 108:3-({[(1R)-6-(3,4-dihydro-2H-1,4-benzoxazin-4-yl)-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 86% yield from Preparation 108caccording to the procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ1.65-1.70 (1H, m), 1.79-1.85 (3H, m), 2.69-2.73 (2H, m), 3.08-3.11 (1H,m), 3.43-3.49 (1H, m), 3.58-3.65 (3H, m), 4.22 (2H, t, J=4.0 Hz),6.67-6.71 (2H, m), 6.76-6.81 (2H, m), 6.97-7.01 (2H, m), 7.31 (1H, d,J=8.0 Hz), 7.57 (1H, d, J=4.8 Hz), 7.84 (1H, d, J=4.8 Hz), 8.37 (1H, s).[M+H] Calc'd for C₂₅H₂₅N₃O₃, 416; Found, 416.

Preparation 109a: 3,5-difluoro-N-methylaniline

A solution of 3,5-difluoroaniline (5.0 g, 38.7 mmol) in HCOOH (15 mL)was heated to reflux for 4 h. The mixture was poured into ice-water andstirred for 0.5 h. The white solid was collected by filtration, anddried under vacuum to give 4.8 g (79%) of crudeN-(3,5-difluorophenyl)formamide.

To the solution of LiAlH₄ (3.0 g, 78.9 mmol) in dry THF (50 mL) wasadded a solution of N-(3,5-difluorophenyl)formamide (4.8 g, 30.6 mmol)in dry THF (50 mL) at r.t. The mixture was stirred overnight and thenquenched with addition of water (3.0 mL), aqueous 10% NaOH (3.0 mL), andwater (9.0 ml). The reaction mixture was filtered and extracted withEtOAc. Organics were dried (Na₂SO₄), and concentrated to give 3.8 g(86%) of the title compound as a pale brown oil.

Preparation 109b: Tert-ButylN-{[(4R)-7-[(3,5-difluorophenyl)(methyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}carbamate

The title compound was prepared in 74% yield from Preparation 18d andPreparation 109a according to the general procedure for Preparation 6e.[M+H] calc'd for C₂₂H₂₆₇F₂N₂O₃, 405; found 405.

Preparation 109c:(4R)-4-(aminomethyl)-N-(3,5-difluorophenyl)-N-methyl-3,4-dihydro-2H-1-benzopyran-7-amine

The title compound was prepared in 94% yield from Preparation 109baccording to the procedure for Preparation 43b. [M+H] Calc'd forC₁₇H₁₈F₂N₂O, 305; Found, 305.

Preparation 109d:3-({[(4R)-7-[(3,5-difluorophenyl)(methyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 38% yield from Preparation 109caccording to the procedure for Preparation 4d. [M+H] Calc'd forC₂₄H₂₃F₂N₃O₃, 440; Found, 440.

Example 109:3-({[(4R)-7-[(3,5-difluorophenyl)(methyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 86% yield from Preparation 109caccording to the procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ1.88-1.92 (1H, m), 1.98-2.05 (1H, m), 3.12-3.18 (1H, m), 3.21 (3H, s),3.51-3.56 (1H, m), 3.71-3.75 (1H, m), 4.15-4.27 (2H, m), 6.34-6.37 (2H,m), 6.45-6.50 (1H, m), 6.63 (1H, d, J=2.4 Hz), 6.71 (1H, dd, J=2.0, 8.0Hz), 7.35 (1H, d, J=8.4 Hz), 7.57 (1H, d, J=5.2 Hz), 7.84 (1H, d, J=5.2Hz), 8.42 (1H, s). [M+H] Calc'd for C₂₃H₂₁F₂N₃O₃, 426; Found, 426.

Preparation 110a: Tert-ButylN-{[(4R)-7-[(3-chlorophenyl)(methyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}carbamate

The title compound was prepared in 37% yield from Preparation 18d and3-chloro-N-methylaniline according to the general procedure forPreparation 6e. [M+H] calc'd for C₂₂H₂₇ClN₂O₃, 403; found 403.

Preparation 110b:(4R)-4-(aminomethyl)-N-(3-chlorophenyl)-N-methyl-3,4-dihydro-2H-1-benzopyran-7-amine

The title compound was prepared in 79% yield from Preparation 110aaccording to the procedure for Preparation 43b. [M+H] Calc'd forC₁₇H₁₉ClN₂O, 303; Found, 303.

Preparation 110c:3-({[(4R)-7-[(3-chlorophenyl)(methyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 50% yield from Preparation 110baccording to the procedure for Preparation 4d. [M+H] Calc'd forC₂₄H₂₄ClN₃O₃, 438; Found, 438.

Example 110:3-({[(4R)-7-[(3-chlorophenyl)(methyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 82% yield from Preparation 110caccording to the procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ1.86-1.90 (1H, m), 1.98-2.02 (1H, m), 3.10-3.14 (1H, m), 3.21 (3H, s),3.48-3.54 (1H, m), 3.68-3.73 (1H, m), 4.16-4.24 (2H, m), 6.52 (1H, s),6.62-6.64 (1H, m), 6.79-6.85 (3H, m), 7.21 (1H, t, J=8.0 Hz), 7.29 (1H,d, J=8.0 Hz), 7.57 (1H, d, J=5.2 Hz), 7.85 (1H, d, J=5.2 Hz), 8.42 (1H,s). [M+H] Calc'd for C₂₃H₂₂ClN₃O₃, 424; Found, 424.

Preparation 111a: Tert-ButylN-{[(4R)-7-[methyl(2-methylphenyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}carbamate

The title compound was prepared in 27% yield from Preparation 18d andN,2-dimethylaniline according to the general procedure for Preparation9a. [M+H] calc'd for C₂₃H₃₀N₂O₃, 383; found 383.

Preparation 111b:(4R)-4-(aminomethyl)-N-methyl-N-(2-methylphenyl)-3,4-dihydro-2H-1-benzopyran-7-amine

The title compound was prepared in 96% yield from Preparation 111aaccording to the procedure for Preparation 43b. [M+H] Calc'd forC₁₈H₂₂N₂O, 283; Found, 283.

Preparation 111c: Methyl3-({[(4R)-7-[methyl(2-methylphenyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 11% yield from Preparation 111baccording to the procedure for Preparation 4d. [M+H] Calc'd forC₂₅H₂₇N₃O₃, 418; Found, 418.

Example 111:3-({[(4R)-7-[methyl(2-methylphenyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 58% yield from Preparation 111caccording to the procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ1.83-1.93 (1H, m), 1.94-1.96 (1H, m), 2.07 (3H, m), 2.97-3.01 (1H, m),3.11 (3H, s), 3.37-3.45 (1H, m), 3.58-3.62 (1H, m), 4.05-4.15 (2H, m),5.84 (1H, s), 5.98-6.00 (1H, m), 7.04 (1H, d, J=8.8 Hz), 7.09-7.11 (1H,m), 7.18-7.32 (3H, m), 7.56 (1H, t, J=5.2 Hz), 7.83 (1H, d, J=4.8 Hz),8.38 (1H, s). [M+H] Calc'd for C₂₄H₂₅N₃O₃, 404; Found, 404.

Preparation 112a: 4-fluoro-3-methoxy-N-methylaniline

The title compound was prepared in 75% yield from4-fluoro-3-methoxy-aniline according to the general procedure forPreparation 109a.

Preparation 112b: Tert-ButylN-{[(4R)-7-[(4-fluoro-3-methoxyphenyl)(methyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}carbamate

The title compound was prepared in 49% yield from Preparation 18d andPreparation 112a according to the general procedure for Preparation 9a.[M+H] calc'd for C₂₃H₂₉FN₂O₄, 417; found 417.

Preparation 112c:(4R)-4-(aminomethyl)-N-(4-fluoro-3-methoxyphenyl)-N-methyl-3,4-dihydro-2H-1-benzopyran-7-amine

The title compound was prepared in 94% yield from Preparation 112baccording to the procedure for Preparation 43b. [M+H] Calc'd forC₁₈H₂₁FN₂O₂, 317; Found, 317.

Preparation 112d: Methyl3-({[(4R)-7-[(4-fluoro-3-methoxyphenyl)(methyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 66% yield from Preparation 112caccording to the procedure for Preparation 4d. [M+H] Calc'd forC₂₅H₂₆FN₃O₄, 450; Found, 450.

Example 112:3-({[(4R)-7-[(4-fluoro-3-methoxyphenyl)(methyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 78% yield from Preparation 112daccording to the procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ1.82-1.87 (1H, m), 1.91-2.00 (1H, m), 3.03-3.07 (1H, m), 3.18 (3H, s),3.43-3.50 (1H, m), 3.61-3.68 (1H, m), 3.78 (3H, s), 4.08-4.18 (2H, m),6.27 (1H, d, J=2.4 Hz), 6.41 (1H, dd, J=8.4, 2.4 Hz), 6.54-6.58 (1H, m),6.82-6.85 (1H, m), 7.09-7.16 (2H, m), 7.56 (1H, d J=5.2 Hz), 7.84 (1H,d, J=5.2 Hz), 8.39 (1H, s). [M+H] Calc'd for C₂₄H₂₄FN₃O₄, 438; Found,438.

Preparation 113a: Tert-ButylN-{[(1R)-6-[methyl(oxan-4-yl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}carbamate

To a solution of Preparation 6d (400 mg, 1.18 mmol) in toluene (10 mL)was added N-methyloxan-4-amine (270 mg, 2.36 mmol), Cs₂CO₃ (770 mg, 2.36mmol), BINAP (38 mg, 0.06 mmol) and Pd(OAc)₂ (14 mg, 0.06 mmol). Themixture was stirred overnight at 100° C. under N₂. The mixture wasfiltered and concentrated, and the residue was purified by HPLC to give70 mg (15%) of the title compound as a yellow gum. [M+H] Calc'd forC₂₂H₃₄N₂O₃, 375; Found, 375.

Preparation 113b:N-[(5R)-5-(aminomethyl)-5,6,7,8-tetrahydronaphthalen-2-yl]-N-methyloxan-4-amine

The title compound was prepared in 99% yield from Preparation 113aaccording to the procedure for Preparation 43b. [M+H] Calc'd forC₁₇H₂₆N₂O, 275; Found, 275.

Preparation 113c: Methyl3-({[(1R)-6-[methyl(oxan-4-yl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 26% yield from Preparation 113baccording to the procedure for Preparation 4d. [M+H] Calc'd forC₂₄H₃₁N₃O₃, 410; Found, 410.

Example 113:3-({[(1R)-6-[methyl(oxan-4-yl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 10% yield from Preparation 113caccording to the procedure for Example 1. ¹H NMR (300 MHz, DMSO-d₆): δ1.61-1.68 (3H, m), 1.83-2.06 (6H, m), 2.87-2.94 (2H, m), 3.25 (3H, s),3.34-3.44 (2H, m), 3.62-3.65 (2H, m), 3.81-3.90 (1H, m), 4.01-4.06 (2H,m), 7.28-7.30 (2H, m), 7.51 (1H, d, J=7.8 Hz), 7.89-7.91 (1H, m), 8.08(1H, d, J=5.4 Hz), 8.26 (1H, d, J=1.8 Hz). [M+H] Calc'd for C₂₃H₂₉N₃O₃,396; Found, 396.

Preparation 114a: Tert-ButylN-{[(1R)-6-[(4-fluoro-3-methoxyphenyl)(methyl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}carbamate

The title compound was prepared in 41% yield from Preparation 6d andPreparation 112a according to the general procedure for Preparation 6e.[M+H] calc'd for C₂₄H₃₁FN₂O₃, 415; found 415.

Preparation 114b:(5R)-5-(aminomethyl)-N-(4-fluoro-3-methoxyphenyl)-N-methyl-5,6,7,8-tetrahydronaphthalen-2-amine

The title compound was prepared in 85% yield from Preparation 114aaccording to the procedure for Preparation 43b. [M+H] Calc'd forC₁₉H₂₃FN₂O, 315; Found, 315.

Preparation 114c: Methyl3-({[(1R)-6-[(4-fluoro-3-methoxyphenyl)(methyl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 62% yield from Preparation 114baccording to the procedure for Preparation 4d. [M+H] Calc'd forC₂₆H₂₈FN₃O₃, 450; Found, 450.

Example 114:3-({[(1R)-6-[(4-fluoro-3-methoxyphenyl)(methyl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 98% yield from Preparation 114caccording to the procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ1.64-1.84 (4H, m), 2.64-2.68 (2H, m), 3.03-3.06 (1H, m), 3.21 (3H, s),3.38-3.45 (1H, m), 3.54-3.58 (1H, m), 3.76 (3H, s), 6.46-6.50 (1H, m),6.70-6.78 (3H, m), 7.06-7.11 (1H, m), 7.20 (1H, d, J=8.4 Hz), 7.56 (1H,t, J=5.2 Hz), 7.82 (1H, d, J=5.2 Hz), 8.34 (1H, s). [M+H] Calc'd forC₂₅H₂₆FN₃O₃, 436; Found, 436.

Preparation 115a: Tert-ButylN-{[(1R)-6-[(3-cyanophenyl)(methyl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}carbamate

The title compound was prepared in 36% yield from Preparation 6e and3-cyano-N-methylaniline according to the general procedure forPreparation 9a. [M+H] calc'd for C₂₄H₂₉N₃O₂, 392; found 392.

Preparation 115b:3-{[(5R)-5-(aminomethyl)-5,6,7,8-tetrahydronaphthalen-2-yl](methyl)amino}benzonitrile

The title compound was prepared in 97% yield from Preparation 115aaccording to the procedure for Preparation 43b. [M+H] Calc'd forC₁₉H₂₁N₃, 292; Found, 292.

Preparation 115c: Methyl3-({[(1R)-6-[(3-cyanophenyl)(methyl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 69% yield from Preparation 115baccording to the procedure for Preparation 4d. [M+H] Calc'd forC₂₆H₂₆N₄O₂, 427; Found, 427.

Example 115:3-({[(1R)-6-[(3-cyanophenyl)(methyl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 76% yield from Preparation 115caccording to the procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ1.66-1.87 (4H, m), 2.72-2.74 (2H, m), 3.11-3.17 (1H, m), 3.25 (3H, s),3.51-3.53 (1H, m), 3.62-3.65 (1H, m), 6.95-6.96 (2H, m), 7.02-7.04 (1H,m), 7.12-7.16 (2H, m), 7.32-7.37 (2H, m), 7.77 (1H, d, J=5.2 Hz), 7.91(1H, t, J=5.6 Hz), 8.42 (1H, s). [M+H] Calc'd for C₂₅H₂₄N₄O₂, 413;Found, 413.

Preparation 116a: Tert-ButylN-{[(4R)-7-(2-methoxyphenyl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}carbamate

The title compound was prepared in 83% yield from 2-methoxyphenylboronicacid and Preparation 18d according to the procedures for Preparation43a. [M+H] Calc'd for C₂₂H₂₇NO₄, 370; Found, 370.

Preparation 116b:[(4R)-7-(2-methoxyphenyl)-3,4-dihydro-2H-1-benzopyran-4-yl]methanamine

The title compound was prepared in quantitative yield from Preparation116a according to the procedure for Preparation 43b. [M+H] Calc'd forC₁₇H₁₉NO₂, 270; Found, 270.

Preparation 116c: Methyl3-({[(4R)-7-(2-methoxyphenyl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 57% yield from Preparation 116baccording to the procedure for Preparation 4d. [M+H] Calc'd forC₂₄H₂₄N₂O₄, 405; Found, 405.

Example 116:3-({[(4R)-7-(2-methoxyphenyl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 75% yield from Preparation 116caccording to the procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ1.90-1.93 (1H, m), 2.00-2.05 (1H, m), 3.15-3.18 (1H, m), 3.51-3.57 (1H,m), 3.72-3.76 (4H, m), 4.17-4.26 (2H, m), 6.87 (1H, s), 6.94-7.02 (2H,m), 7.09 (1H, d, J=8.0 Hz), 7.24-7.26 (1H, m), 7.30-7.35 (2H, m), 7.58(1H, d, J=4.8 Hz), 7.86 (1H, d, J=5.2 Hz), 8.45 (1H, s). [M+H] Calc'dfor C₂₃H₂₂N₂O₄, 391; Found, 391.

Preparation 117a: Tert-ButylN-{[(4R)-7-[(3-cyanophenyl)(methyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}carbamate

The title compound was prepared in 55% yield from Preparation 18d and3-cyano-N-methylaniline according to the general procedure forPreparation 9a. [M+H] Calc'd for C₂₃H₂₇N₃O₃, 394; Found, 394.

Preparation 117b:3-{[(4R)-4-(aminomethyl)-3,4-dihydro-2H-1-benzopyran-7-yl](methyl)amino}benzonitrile

The title compound was prepared in quantitative yield from Preparation117a according to the procedure for Preparation 43b. [M+H] Calc'd forC₁₈H₁₉N₃O, 294; Found, 294.

Preparation 117c: Methyl3-({[(4R)-7-[(3-cyanophenyl)(methyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 56% yield from Preparation 117baccording to the procedure for Preparation 4d. [M+H] Calc'd forC₂₅H₂₄N₄O₃, 429; Found, 429.

Example 117:3-({[(4R)-7-[(3-cyanophenyl)(methyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 85% yield from Preparation 117caccording to the procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ1.88-1.98 (1H, m), 1.99-2.03 (1H, m), 3.11-3.15 (1H, m), 3.26 (3H, s),3.49-3.54 (1H, m), 3.69-3.74 (1H, m), 4.15-4.25 (2H, m), 6.57 (1H, d,J=2.4 Hz), 6.65-6.68 (1H, m), 7.09-7.12 (1H, m), 7.18-7.20 (2H, m),7.32-7.38 (2H, m), 7.57 (1H, d, J=5.2 Hz), 7.85 (1H, d, J=5.2 Hz), 8.41(1H, s). [M+H] Calc'd for C₂₄H₂₂N₄O₃, 415; Found, 415.

Preparation 118a: Tert-ButylN-{[(4R)-7-(4-fluoro-2-methoxyphenyl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}carbamate

The title compound was prepared in 60% yield from4-fluoro-2-methoxyphenylboronic acid and Preparation 18d according tothe procedures for Preparation 43a. [M+H] Calc'd for C₂₂H₂₆FNO₄, 388;Found, 388. [M+H] Calc'd for C₂₂H₂₆FNO₄, 388; Found, 388.

Preparation 118b:[(4R)-7-(4-fluoro-2-methoxyphenyl)-3,4-dihydro-2H-1-benzopyran-4-yl]methanamine

The title compound was prepared in 95% yield from Preparation 118aaccording to the procedure for Preparation 43b. [M+H] Calc'd forC₁₇H₁₈FN₂O₄, 288; Found, 288.

Preparation 118c: Methyl3-({[(4R)-7-(4-fluoro-2-methoxyphenyl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 63% yield from Preparation 118baccording to the procedure for Preparation 4d. [M+H] Calc'd forC₂₄H₂₃FN₂O₄, 423; Found, 423.

Example 118:3-({[(4R)-7-(4-fluoro-2-methoxyphenyl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 67% yield from Preparation 118caccording to the procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ1.91-2.03 (2H, m), 3.15-3.18 (1H, m), 3.51-3.60 (1H, m), 3.72-3.77 (4H,m), 4.16-4.24 (2H, m), 6.80-6.85 (2H, m), 6.92 (1H, dd, J=1.6, 7.8 Hz),6.99 (1H, dd, J=2.4, 11.2 Hz), 7.25-7.29 (1H, m), 3.34 (1H, d, J=8.0Hz), 7.55 (1H, d, J=5.2 Hz), 7.87 (1H, d, J=5.2 Hz), 8.45 (1H, s). [M+H]Calc'd for C₂₃H₂₁FN₂O₄, 409; Found, 409.

Preparation 119a: Tert-ButylN-{[(4R)-7-[(4-cyanophenyl)(methyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}carbamate

The title compound was prepared in 57% yield from Preparation 18d and4-cyano-N-methylaniline according to the general procedure forPreparation 9a. [M+H] Calc'd for C₂₃H₂₇N₃O₃, 394; Found, 394.

Preparation 119b:4-{[(4R)-4-(aminomethyl)-3,4-dihydro-2H-1-benzopyran-7-yl](methyl)amino}benzonitrile

The title compound was prepared in quantitative yield from Preparation119a according to the procedure for Preparation 43b. [M+H] Calc'd forC₁₈H₁₉N₃O, 294; Found, 294.

Preparation 119c: Methyl3-({[(4R)-7-[(4-cyanophenyl)(methyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 50% yield from Preparation 119baccording to the procedure for Preparation 4d. [M+H] Calc'd forC₂₅H₂₄N₄O₃, 429; Found, 429.

Example 119:3-({[(4R)-7-[(4-cyanophenyl)(methyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 88% yield from Preparation 119caccording to the procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ1.92-1.94 (1H, m), 2.01-2.04 (1H, m), 3.15-3.18 (1H, m), 3.27 (3H, s),3.52-3.57 (1H, m), 3.72-3.76 (1H, m), 4.19-4.25 (2H, m), 6.67 (1H, d,J=2.0 Hz), 6.73-6.79 (3H, m), 7.39 (1H, d, J=8.0 Hz), 7.54-7.59 (3H, m),7.86 (1H, d, J=5.2 Hz), 8.43 (1H, s). [M+H] Calc'd for C₂₄H₂₂N₄O₃, 415;Found, 415.

Preparation 120a: Tert-ButylN-{[(1R)-6-[(cyclopropylmethyl)(methyl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}carbamate

To a solution of Preparation 6d (0.5 g, 1.47 mmol) in toluene (10 mL)was added N-(cyclopropylmethyl)-N-methylamine hydrochloride (0.36 g,2.94 mmol), Pd₂(dba)₃ (28 mg, 0.029 mmol), Xantphos (51 mg, 0.088 mmol)and Cs₂CO₃ (2.4 g, 7.35 mmol). The mixture was heated in a sealed tubeat 130° C. for 4 h. The mixture was filtered and concentrated, and theresidue was purified by silica gel chromatography (PE:EtOAc=9:1 to 4:1)to give 48 mg (9%) of the title compound as a brown oil. [M+H] Calc'dfor C₂₁H₃₂N₂O₂, 345; Found, 345.

Preparation 120b:(5R)-5-(aminomethyl)-N-(cyclopropylmethyl)-N-methyl-5,6,7,8-tetrahydronaphthalen-2-amine

The title compound was prepared in 90% yield from Preparation 120aaccording to the procedure for Preparation 43b. [M+H] Calc'd forC₁₆H₂₄N₂, 245; Found, 245.

Preparation 120c: Methyl3-({[(1R)-6-[(cyclopropylmethyl)(methyl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 38% yield from Preparation 120baccording to the procedure for Preparation 4d. [M+H] Calc'd forC₂₃H₂₉N₃O₂, 380; Found, 380.

Example 120:3-({[(1R)-6-[(cyclopropylmethyl)(methyl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 50% yield from Preparation 120caccording to the procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ0.33-0.37 (2H, m), 0.60-0.65 (2H, m), 0.81-0.88 (1H, m), 1.80-1.87 (1H,m), 1.91-2.05 (3H, m), 2.83-2.98 (2H, m), 3.26 (3H, s), 3.30-3.32 (1H,m), 3.46 (2H, d, J=7.2 Hz), 3.59-3.68 (2H, m), 7.36-7.40 (2H, m), 7.53(1H, d, J=8.4 Hz), 7.94 (1H, s) 8.19 (1H, d, J=5.2 Hz), 8.36 (1H, s).[M+H] Calc'd for C₂₂H₂₇N₃O₂, 366; Found, 366.

Preparation 121a: Tert-ButylN-{[(1R)-6-[(6-methoxypyridin-2-yl)(methyl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}carbamate

The title compound was prepared in 58% yield from Preparation 6d and6-methoxy-N-methylpyridin-2-amine according to the general procedure forPreparation 9a. [M+H] Calc'd for C₂₃H₃₁N₃O₃, 398; Found, 398.

Preparation 121b:N-[(5R)-5-(aminomethyl)-5,6,7,8-tetrahydronaphthalen-2-yl]-6-methoxy-N-methylpyridin-2-amine

The title compound was prepared in quantitative yield from Preparation121a according to the procedure for Preparation 43b. [M+H] Calc'd forC₁₈H₂₃N₃O, 298; Found, 298.

Preparation 121c: Methyl3-({[(1R)-6-[(6-methoxypyridin-2-yl)(methyl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 28% yield from Preparation 121baccording to the procedure for Preparation 4d. [M+H] Calc'd forC₂₅H₂₈N₄O₃, 433; Found, 433.

Example 121:3-({[(1R)-6-[(6-methoxypyridin-2-yl)(methyl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 50% yield from Preparation 121caccording to the procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ1.67-1.87 (4H, m), 2.70-2.74 (2H, m), 3.07-3.09 (1H, m), 3.34-3.36 (4H,m), 3.55-3.61 (1H, m), 3.80 (3H, s), 5.99-6.06 (2H, m), 7.03-7.07 (2H,m), 7.30-7.38 (2H, m), 7.57 (1H, d, J=4.8 Hz), 7.82 (1H, d, J=4.8 Hz),8.54 (1H, s). [M+H] Calc'd for C₂₄H₂₆N₄O₃, 419; Found, 419.

Preparation 122a: Methyl3-({[(1R)-6-bromo-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

To a solution of Preparation 6c (3.2 g, 13.39 mmol) in toluene (50 mL)was added methyl 3-bromo-isonicotinate (3.47 g, 16.07 mmol), Cs₂CO₃(8.73 g, 26.78 mmol), Xantphos (462 mg, 0.8 mmol) and Pd₂(dba)₃ (250 mg,0.27 mmol). The mixture was stirred overnight at 120° C. under nitrogen.The mixture was filtered and concentrated, and the residue was purifiedby prep-HPLC to give 2.53 g (50%) of the title compound as a yellow gum.[M+H] Calc'd for C₁₈H₁₉BrN₂O₂, 375, 377; Found, 375, 377.

Example 122:3-({[(1R)-6-[methyl(5-methylpyridin-2-yl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylicAcid

To a solution of Preparation 122a (550 mg, 1.47 mmol) in toluene (10 mL)was added N,5-dimethylpyridin-2-amine (178 mg, 1.47 mmol), t-BuONa (282mg, 2.94 mmol), JohnPhos (66 mg, 0.22 mmol) and Pd₂(dba)₃ (138 mg, 0.15mmol). The mixture was stirred overnight at 110° C. under nitrogen. Themixture was filtered and concentrated, and the residue was purified byprep-HPLC to 101 mg (16%) as a yellow solid. (Hydrolysis of the esterhad occurred during the course of this reaction.) ¹H NMR (300 MHz,DMSO-d₆): δ 1.64-1.70 (1H, m), 1.77-1.86 (3H, m), 2.10 (3H, s),2.70-2.72 (2H, m), 3.07-3.11 (1H, m), 3.31 (3H, s), 3.40-3.48 (1H, m),3.57-3.63 (1H, m), 6.45 (1H, d, J=8.4 Hz), 6.97 (1H, s), 7.00 (1H, d,J=1.5 Hz), 7.23 (1H, d, J=2.4 Hz), 7.32 (1H, d, J=8.1 Hz), 7.55 (1H, d,J=5.1 Hz), 7.81 (1H, d, J=4.8 Hz), 7.96 (1H, s), 8.33 (1H, s). [M+H]Calc'd for C₂₄H₂₆N₄O₂, 403; Found, 403.

Preparation 123a: Tert-ButylN-{[(1R)-6-[methyl(6-methylpyridin-2-yl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}carbamate

The title compound was prepared in 30% yield from Preparation 6d andN,6-dimethylpyridin-2-amine according to the general procedure forPreparation 9a. [M+H] Calc'd for C₂₃H₃₁N₃O₂, 382; Found, 382.

Preparation 123b:N-[(5R)-5-(aminomethyl)-5,6,7,8-tetrahydronaphthalen-2-yl]-N,6-dimethylpyridin-2-amine

The title compound was prepared in quantitative yield from Preparation123a according to the procedure for Preparation 43b. [M+H] Calc'd forC₁₈H₂₃N₃, 282; Found, 282.

Preparation 123c: Methyl3-({[(1R)-6-[methyl(6-methylpyridin-2-yl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 56% yield from Preparation 123baccording to the procedure for Preparation 4d. [M+H] Calc'd forC₂₅H₂₈N₄O₂, 417; Found, 417.

Example 123:3-({[(1R)-6-[methyl(6-methylpyridin-2-yl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 35% yield from Preparation 123caccording to the procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ1.67-1.70 (1H, m), 1.82-1.84 (3H, m), 2.34 (3H, s), 2.70-2.74 (2H, m),3.07-3.09 (1H, m), 3.34-3.36 (4H, m), 3.53-3.58 (1H, m), 6.27 (1H, d,J=8.4 Hz), 6.49 (1H, d, J=7.2 Hz), 6.99-7.02 (2H, m), 7.27 (1H, dd,J=7.2, 8.0 Hz), 7.36 (1H, d, J=8.0 Hz), 7.57 (1H, d, J=4.4 Hz), 7.60(1H, d, J=4.8 Hz), 8.20 (1H, s). [M+H] Calc'd for C₂₄H₂₆N₄O₂, 403;Found, 403.

Preparation 124a: Tert-ButylN-{[(4R)-7-(2-cyanophenyl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}carbamate

The title compound was prepared in 29% yield from Preparation 18d and2-cyanophenylboronic acid according to the general procedure outlinedfor Preparation 43a. [M+H] Calc'd for C₂₂H₂₄N₂O₃, 365; Found, 365.

Preparation 124b:2-[(4R)-4-(aminomethyl)-3,4-dihydro-2H-1-benzopyran-7-yl]benzonitrile

The title compound was prepared in quantitative yield from Preparation124a according to the procedure for Preparation 43b. [M+H] Calc'd forC₁₇H₁₆N₂O, 265; Found, 265.

Preparation 124c: Methyl3-({[(4R)-7-(2-cyanophenyl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 24% yield from Preparation 124baccording to the procedure for Preparation 4d. [M+H] Calc'd forC₂₄H₂₁N₃O₃, 400; Found, 400.

Example 124:3-({[(4R)-7-(2-cyanophenyl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 54% yield from Preparation 124caccording to the procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ1.92-2.06 (2H, m), 3.21-3.26 (1H, m), 3.54-3.60 (1H, m), 3.76-3.81 (1H,m), 4.21-4.28 (2H, m), 6.99 (1H, d, J=1.6 Hz), 7.06-7.09 (1H, m), 7.50(1H, d, J=8.4 Hz), 7.55-7.61 (3H, m), 7.75-7.79 (1H, m), 7.87 (1H, d,J=4.8 Hz), 7.93 (1H, d, J=6.4 Hz), 8.47 (1H, s). [M+H] Calc'd forC₂₃H₁₉N₃O₃, 386; Found, 386.

Preparation 125a: Tert-ButylN-{[(1R)-6-[methyl(1-methyl-1H-pyrazol-3-yl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}carbamate

The title compound was prepared in 62% yield from Preparation 6d andNJ-dimethyl-1H-pyrazol-3-amine according to the general procedure forPreparation 9a. [M+H] Calc'd for C₂₁H₃₀N₄O₂, 371; Found, 371.

Preparation 125b:N-[(5R)-5-(aminomethyl)-5,6,7,8-tetrahydronaphthalen-2-yl]-N,1-dimethyl-1H-pyrazol-3-amine

The title compound was prepared in quantitative yield from Preparation125a according to the procedure for Preparation 43b. [M+H] Calc'd forC₁₆H₂₂N₄, 271; Found, 271.

Preparation 125c: Methyl3-({[(1R)-6-[methyl(1-methyl-1H-pyrazol-3-yl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 24% yield from Preparation 125baccording to the procedure for Preparation 4d. [M+H] Calc'd forC₂₃H₂₇N₅O₂, 406; Found, 406.

Example 125:3-({[(1R)-6-[methyl(1-methyl-1H-pyrazol-3-yl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 90% yield from Preparation 125caccording to the procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ1.62-1.82 (4H, m), 2.64-2.71 (2H, m), 3.00-3.05 (1H, m), 3.22 (3H, s),3.37-3.44 (1H, m), 3.52-3.58 (1H, m), 3.72 (3H, s), 5.81 (1H, s), 6.81(1H, s), 6.90 (1H, d, J=8.3 Hz), 7.17 (1H, d, J=8.3 Hz), 7.51 (1H, s),7.57 (1H, br s), 7.83 (1H, br s), 8.35 (1H, br s). [M+H] Calc'd forC₂₂H₂₅N₅O₂, 392; Found, 392.

Preparation 126a: N-methyl-4-[2-(trimethylsilyl)ethynyl]aniline

To a suspension of 4-bromo-N-methylaniline (500 mg, 2.7 mmol),trimethylsilyl acetylene (527 mg, 5.4 mmol), CuI (92 mg, 0.5 mmol) andPPh₃ (233 mg, 0.9 mmol) in TEA (20 mL) was added PdCl₂(PPh₃)₂ (94 mg,0.1 mmol) at r.t. under N₂. The reaction was stirred at refluxovernight. The reaction was filtered, concentrated, and purified bysilica gel chromatography (PE:EtOAc=20:1) to give 200 mg (37%) of thetitle compound as a yellow oil. [M+H] Calc'd for C₁₂H₁₇NSi, 204; Found,204.

Preparation 126b: Methyl3-({[(4R)-7-bromo-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared from Preparation 18c and methyl3-bromo-isonicotinate according to the general procedure outline forPreparation 122a. [M+H] Calc'd for C₁₇H₁₇BrN₂O₃, 377, 379; Found, 377,379.

Preparation 126c: Methyl3-({[(4R)-7-[methyl({4-[2-(trimethylsilyl)ethynyl]phenyl})amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

To a suspension of Preparation 126b (100 mg, 0.27 mmol),N-methyl-4-[2-(trimethylsilyl)-ethynyl]aniline (54 mg, 0.27 mmol),Xantphos (23 mg, 0.04 mmol) and Cs₂CO₃ (123 mg, 0.38 mmol) in toluene(10 mL) was added Pd₂dba₃ (12 mg, 0.01 mmol) at r.t. under N₂. Thereaction was stirred at 110° C. overnight. The reaction was filtered,concentrated, and purified by silica gel chromatography (PE:EtOAc=5:1)to give 30 mg (23%) of the title compound as a yellow oil. [M+H] Calc'dfor C₂₉H₃₃N₃O₃Si, 500; Found, 500.

Preparation 126d: Methyl3-({[(4R)-7-[(4-ethynylphenyl)(methyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

To a solution of Preparation 126c (50 mg, 0.10 mmol) in THF (5 mL) wasadded TBAF (0.20 mL, 1.0 M in THF, 0.20 mmol), and the reaction wasstirred at r.t. for 1 h. The solution was concentrated and dried undervacuum. This material was used for the next step directly withoutpurification. [M+H] Calc'd for C₂₆H₂₅N₃O₃, 428; Found, 428.

Example 126:3-({[(4R)-7-[(4-ethynylphenyl)(methyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 49% yield from Preparation 126daccording to the procedure for Example 1. ¹H NMR (300 MHz, DMSO-d₆): δ1.83-1.88 (1H, m), 1.94-2.03 (1H, m), 3.09-3.12 (1H, m), 3.19 (3H, s),3.49-3.51 (1H, m), 3.67-3.72 (1H, m), 3.94 (1H, s), 4.17-4.21 (2H, m),6.55 (1H, d, J=1.8 Hz), 6.63 (1H, dd, J=1.8, 8.1 Hz), 6.80 (2H, d, J=8.7Hz), 7.28-7.31 (3H, m), 7.57 (1H, d, J=4.8 Hz), 7.84 (1H, d, J=5.1 Hz),8.40 (1H, s). [M+H] Calc'd for C₂₅H₂₃N₃O₃, 414; Found, 414.

Preparation 127a: N-methyl-1,3-dihydro-2-benzofuran-5-amine

1,3-Dihydro-2-benzofuran-5-amine (300 mg, 2.2 mmol) was added to HCOOH(10 mL), and the reaction was stirred at reflux overnight. The reactionwas concentrated, basified to pH=8 with sat Na₂CO₃, and extracted withEtOAc. Organics were washed with brine, dried (Na₂SO₄), and concentratedto give 250 mg (69%) of N-(1,3-dihydro-2-benzofuran-5-yl)formamide as ayellow oil.

To a solution of N-(1,3-dihydro-2-benzofuran-5-yl)formamide (250 mg, 1.5mmol) in THF (20 mL) was added LAH (1.9 mL, 2.4 M in THF, 4.6 mmol) at0° C. The reaction was stirred at r.t. for 2 h. The solution was dilutedwith water (0.5 mL) and EtOAc (30 mL), dried (Na₂SO₄), and concentratedto give 220 mg (96%) of the title compound as a yellow oil. [M+H] Calc'dfor C₉H_(ii)NO, 150; Found, 150.

Preparation 127b: Methyl3-({[(4R)-7-[(1,3-dihydro-2-benzofuran-5-yl)(methyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 40% yield from Preparation 126b andN-methyl-1,3-dihydro-2-benzofuran-5-amine according to the generalprocedure outlined for Preparation 126c. [M+H] Calc'd for C₂₆H₂₇N₃O₄,446; Found, 446.

Example 127:3-({[(4R)-7-[(1,3-dihydro-2-benzofuran-5-yl)(methyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 90% yield from Preparation 127baccording to the procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ1.84-1.87 (1H, m), 1.96-1.99 (1H, m), 3.04-3.08 (1H, m), 3.19 (3H, s),3.44-3.50 (1H, m), 3.64-3.69 (1H, m), 4.10-4.18 (2H, m), 4.95 (4H, s),6.32 (1H, d, J=2.8 Hz), 6.45 (1H, dd, J=2.4, 8.4 Hz), 6.91-6.97 (2H, m),7.16-7.22 (2H, m), 7.57 (1H, d, J=4.8 Hz), 7.84 (1H, d, J=5.2 Hz), 8.40(1H, s). [M+H] Calc'd for C₂₅H₂₅N₃O₄, 432; Found, 432.

Preparation 128a: Tert-ButylN-{[(4R)-7-{methyl[4-(trifluoromethyl)phenyl]amino}-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}carbamate

The title compound was prepared in 23% yield from Preparation 18d andN-methyl-4-(trifluoromethyl)aniline according to the general procedureoutlined for Preparation 9a. [M+H] Calc'd for C₂₃H₂₇F₃N₂O₃, 437; Found,437.

Preparation 128b:(4R)-4-(aminomethyl)-N-methyl-N-[4-(trifluoromethyl)phenyl]-3,4-dihydro-2H-1-benzopyran-7-amine

The title compound was prepared in 95% yield from Preparation 128aaccording to the procedure for Preparation 43b. [M+H] Calc'd forC₁₈H₁₉F₃N₂O, 337; Found, 337.

Preparation 128c: Methyl3-({[(4R)-7-{methyl[4-(trifluoromethyl)phenyl]amino}-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 60% yield from Preparation 128baccording to the procedure for Preparation 4d. [M+H] Calc'd forC₂₅H₂₄F₃N₃O₃, 472; Found, 472.

Preparation 128:3-({[(4R)-7-{methyl[4-(trifluoromethyl)phenyl]amino}-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 16% yield from Preparation 128caccording to the procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ1.88-1.92 (1H, m), 1.96-2.05 (1H, m), 3.13-3.18 (1H, m), 3.37 (3H, s),3.51-3.56 (1H, m), 3.71-3.76 (1H, m), 4.15-4.27 (2H, m), 6.64 (1H, s),6.71-6.74 (1H, m), 6.88 (2H, d, J=8.4 Hz), 7.37-7.34 (1H, m), 7.48 (2H,d, J=8.8 Hz), 7.58 (1H, d, J=4.8 Hz), 7.85 (1H, d, J=5.2 Hz), 8.43 (1H,s). [M+H] Calc'd for C₂₄H₂₂F₃N₃O₃, 458; Found, 458.

Preparation 129a: N-(2,2,2-trifluoroethyl)aniline

To a solution of aniline (10.0 g, 107 mmol) in DCM (50 mL) was addedTFAA (24.8 g, 118 mmol) and TEA (22 mL, 160 mmol). The mixture wasstirred at r.t. for 2 h. The reaction was washed with water, dried(Na₂SO₄), and concentrated to give 17.7 g (87%) of2,2,2-trifluoro-N-phenylacetamide as a white solid.

To a solution of 2,2,2-trifluoro-N-phenylacetamide (5.0 g, 26 mmol) inTHF (10 mL) was added BH₃ in THF (130 mL, 130 mmol, 1.0 M). Theresulting mixture was refluxed overnight. The mixture was quenched withwater and methanol, concentrated to remove most of THF, and extractedwith EtOAc. Organics were washed with brine, dried (Na₂SO₄), andconcentrated to give 4.17 g (92%) of the title compound as a colorlessoil. ¹H NMR (400 MHz, CDCl₃): δ 3.71-3.75 (2H, m), 6.66 (2H, d, J=8.0Hz), 6.79 (1H, t, J=7.2 Hz), 7.20 (2H, t, J=8.0 Hz).

Preparation 129b: Methyl3-[({7-[phenyl(2,2,2-trifluoroethyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl}methyl)amino]pyridine-4-carboxylate

The title compound was prepared in 4% yield from Preparation 14c andPreparation 129a according to the general procedure for Preparation 15a.[M+H] Calc'd for C₂₅H₂₆F₃N₃O₃, 472; Found, 472.

Example 129:3-[({7-[phenyl(2,2,2-trifluoroethyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl}methyl)amino]pyridine-4-carboxylicAcid

The title compound was prepared in 44% yield from Preparation 129baccording to the procedure for Example 1. ¹H NMR (400 MHz, MeOD-d₄): δ1.90-1.95 (1H, m), 2.05-2.11 (1H, m), 3.08-3.12 (1H, m), 3.43-3.48 (1H,m), 3.58-3.63 (1H, m), 4.06-4.14 (1H, m), 4.24-4.30 (1H, m), 5.24 (2H,t, J=4.6 Hz), 6.29 (1H, d, J=3.2 Hz), 6.36 (1H, d, J=6.0 Hz), 6.92-6.98(3H, m), 7.04 (1H, d, J=8.1 Hz), 7.18-7.22 (2H, m), 7.80-7.82 (1H, m),8.03-8.05 (1H, m), 8.23 (1H, d, J=2.0 Hz). [M+H] Calc'd forC₂₄H₂₂F₃N₃O₃, 458; Found, 458.

Preparation 130a: Tert-ButylN-({7-[benzyl(methyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl}methyl)carbamate

To a solution of tert-butylN-[(7-bromo-3,4-dihydro-2H-1-benzopyran-4-yl)methyl]carbamate (500 mg,1.46 mmol) in toluene (10 mL) was added N-methyl-benzylamine (212 mg,1.75 mmol), Cs₂CO₃ (950 mg, 2.92 mmol), BINAP (44 mg, 0.07 mmol) andPd(OAc)₂ (16 mg, 0.07 mmol). The mixture was stirred overnight at 100°C. under nitrogen. The mixture was filtered and concentrated, and theresidue was purified by prep-HPLC to give 362 mg (65%) of the titlecompound as a colorless gum. [M+H] Calc'd for C₂₃H₃₀N₂O₃, 383; Found,383.

Preparation 130b:4-(aminomethyl)-N-benzyl-N-methyl-3,4-dihydro-2H-1-benzopyran-7-amine

The title compound was prepared in 97% yield from Preparation 130aaccording to the procedure for Preparation 43b. [M+H] Calc'd forC₁₈H₂₂N₂O, 283; Found, 283.

Preparation 130c: Methyl3-({[(1R)-6-[benzyl(methyl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 4% yield from Preparation 130baccording to the general procedure for Preparation 1e. [M+H] Calc'd forC₂₅H₂₇N₃O₃, 418; Found, 418.

Example 130:3-({[(1R)-6-[benzyl(methyl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 76% yield from Preparation 130caccording to the procedure for Example 1. ¹H NMR (400 MHz, MeOD-d₄): δ1.84-1.93 (1H, m), 2.00-2.09 (1H, m), 3.04 (3H, s), 3.10-3.15 (1H, m),3.44-3.50 (1H, m), 3.57-3.62 (1H, m), 4.08-4.18 (2H, m), 4.51 (2H, s),6.47 (1H, d, J=2.0 Hz), 6.53 (1H, d, J=6.0 Hz), 7.12-7.14 (3H, m),7.20-7.22 (3H, m), 7.84 (1H, s), 8.15 (1H, d, J=4.4 Hz), 8.29 (1H, m).[M+H] Calc'd for C₂₄H₂₅N₃O₃, 404; Found, 404.

Preparation 131a: N-methyl-2,3-dihydro-1H-inden-5-amine

The title compound was prepared in 16% overall yield from2,3-dihydro-1H-inden-5-amine according to the general procedure outlinedfor Preparation 127a. [M+H] Calc'd for C₁₀H₁₃N, 148; Found, 148.

Preparation 131b: Tert-ButylN-{[(4R)-7-[(2,3-dihydro-1H-inden-5-yl)(methyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}carbamate

The title compound was prepared in 73% yield from Preparation 18d andPreparation 131a according to the general procedure outlined forPreparation 6e. [M+H] Calc'd for C₂₅H₃₂N₂O₃, 409; Found, 409.

Preparation 131c:(4R)-4-(aminomethyl)-N-(2,3-dihydro-1H-inden-5-yl)-N-methyl-3,4-dihydro-2H-1-benzopyran-7-amine

The title compound was prepared in 98% yield from Preparation 131baccording to the procedure for Preparation 43b. [M+H] Calc'd forC₂₀H₂₄N₂O, 309; Found, 309.

Preparation 131d: Methyl3-({[(4R)-7-[(2,3-dihydro-1H-inden-5-yl)(methyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 51% yield from Preparation 131caccording to the procedure for Preparation 4d. [M+H] Calc'd forC₂₇H₂₉N₃O₃, 444; Found, 444.

Example 131:3-({[(4R)-7-[(2,3-dihydro-1H-inden-5-yl)(methyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 24% yield from Preparation 131daccording to the procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ1.84-1.85 (1H, m), 1.95-2.05 (3H, m), 2.79-2.83 (4H, m), 3.03-3.05 (1H,m), 3.15 (3H, s), 3.43-3.48 (1H, m), 3.62-3.66 (1H, m), 4.09-4.16 (2H,m), 6.20 (1H, d, J=2.4 Hz), 6.35 (1H, d, J=6.0 Hz), 6.81 (1H, d, J=6.0Hz), 6.94 (1H, s), 7.09-7.16 (2H, m), 7.59 (1H, d, J=5.2 Hz), 7.84 (1H,d, J=4.8 Hz), 8.40 (1H, s). [M+H] Calc'd for C₂₆H₂₇N₃O₃, 430; Found,430.

Preparation 132a: Tert-ButylN-{[(1R)-6-[(1,3-dihydro-2-benzofuran-5-yl)(methyl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}carbamate

The title compound was prepared in 48% yield from Preparation 18d andPreparation 127a according to the general procedure outlined forPreparation 9a. [M+H] Calc'd for C₂₅H₃₂N₂O₃, 409; Found, 409.

Preparation 132b:N-[(5R)-5-(aminomethyl)-5,6,7,8-tetrahydronaphthalen-2-yl]-N-methyl-1,3-dihydro-2-benzofuran-5-amine

The title compound was prepared in quantitative yield from Preparation132a according to the procedure for Preparation 43b. [M+H] Calc'd forC₂₀H₂₄N₂O, 309; Found, 309.

Preparation 132c: Methyl3-({[(1R)-6-[(1,3-dihydro-2-benzofuran-5-yl)(methyl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 60% yield from Preparation 132baccording to the procedure for Preparation 4d. [M+H] Calc'd forC₂₇H₂₉N₃O₃, 444; Found, 444.

Example 132:3-({[(1R)-6-[(1,3-dihydro-2-benzofuran-5-yl)(methyl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 84% yield from Preparation 132caccording to the procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ1.65-1.84 (4H, m), 2.64-2.68 (2H, m), 3.03-3.06 (1H, m), 3.21 (3H, s),3.40-3.46 (1H, m), 3.55-3.60 (1H, m), 4.93 (4H, s), 6.74-6.78 (2H, m),6.84-6.89 (2H, m), 7.15-7.23 (2H, m), 7.56 (1H, d, J=4.8 Hz), 7.83 (1H,d, J=5.2 Hz), 8.34 (1H, s). [M+H] Calc'd for C₂₆H₂₇N₃O₃, 430; Found,430.

Preparation 133a: Methyl3-({[(1R)-6-[cyclopentyl(methyl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

To a suspension of Preparation 14a (300 mg, 0.80 mmol),N-methylcyclopentanamine (87 mg, 0.88 mmol), Xantphos (69 mg, 0.12 mmol)and Cs₂CO₃ (365 mg, 1.12 mmol) in toluene (20 mL) was added Pd₂dba₃ (37mg, 0.04 mmol) at r.t. under N₂. The reaction was stirred at 110° C.overnight. The reaction was filtered, concentrated, and purified bysilica gel chromatography (PE:EtOAc=5:1) to give 20 mg (6%) of the titlecompound as a yellow oil. [M+H] Calc'd for C₂₃H₂₉FN₃O₃, 396; Found, 396.

Example 133:3-({[(1R)-6-[cyclopentyl(methyl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 48% yield from Preparation 133aaccording to the procedure for Example 1. ¹H NMR (300 MHz, CD₃OD): δ1.32-1.34 (2H, m), 1.68-1.72 (3H, m), 1.84-1.87 (3H, m), 2.06-2.11 (1H,m), 2.20-2.22 (1H, m), 3.28 (3H, s), 3.34-3.40 (1H, m), 3.66-3.71 (1H,m), 3.79-3.84 (1H, m), 4.16-4.19 (1H, m), 4.33-4.38 (2H, m), 7.16-7.18(2H, m), 7.76 (1H, d, J=5.7 Hz), 8.02 (1H, d, J=4.2 Hz), 8.32 (1H, d,J=4.2 Hz), 8.50 (1H, s). [M+H] Calc'd for C₂₂H₂₇FN₃O₃, 382; Found, 382.

Preparation 134a: 4-cyclopropyl-N-methylaniline

To a suspension of 4-bromo-N-methylaniline (500 mg, 2.69 mmol),cyclopropylboronic acid (462 mg, 5.38 mmol), (cyclohexyl)₃P⁺HBF₄ ⁻ (99mg, 0.27 mmol) and K₃PO₄ (2.0 g, 9.4 mmol) in toluene (20 mL) and H₂O (1mL) was added Pd(OAc)₂ (36 mg, 0.16 mmol) at r.t. under N₂. The reactionwas stirred at reflux overnight. The reaction was filtered,concentrated, and purified by silica gel chromatography (PE:EtOAc=10:1)to give 268 mg (68%) of the title compound as a brown oil. [M+H] Calc'dfor C₁₀H₂₃N, 148; Found, 148.

Preparation 134b: Methyl3-({[(4R)-7-[(4-cyclopropylphenyl)(methyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 4% yield from Preparation 126b and4-cyclopropyl-N-methylaniline according to the general procedureoutlined for Preparation 126c. [M+H] Calc'd for C₂₇H₂₉N₃O₃, 444; Found,444.

Example 134:3-({[(4R)-7-[(4-cyclopropylphenyl)(methyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 28% yield from Preparation 134baccording to the procedure for Example 1. ¹H NMR (300 MHz, DMSO-d₆): δ0.60-0.63 (2H, m), 0.88-0.92 (2H, m), 1.85-1.89 (3H, m), 3.03-3.05 (1H,m), 3.19 (3H, s), 3.45-3.48 (1H, m), 3.62-3.66 (1H, m), 4.10-4.16 (2H,m), 6.24 (1H, d, J=2.4 Hz), 6.24-6.39 (1H, m), 6.93-7.03 (4H, m), 7.12(1H, d, J=8.4 Hz), 7.56 (1H, d, J=5.2 Hz), 7.84 (1H, d, J=5.2 Hz), 8.38(1H, s). [M+H] Calc'd for C₂₆H₂₇N₃O₃, 430; Found, 430.

Preparation 135a: N-methyl-1-benzofuran-6-amine

A mixture of 6-bromo-1-benzofuran (1.0 g, 5.1 mmol), methylamine (2N, 25mL, 50 mmol), CuI (1.16 g, 6.1 mmol) and KOAc (1.25 g, 12.7 mmol) in DMF(10 mL) was stirred overnight at 100° C. under nitrogen in a sealedtube. The mixture was cooled to r.t., diluted with aqueous ammoniumhydroxide, and extracted with EtOAc. The organic layer was concentrated,and the residue was purified by silica gel chromatography to give 250 mg(33%) of the title compound as a yellow oil. [M+H] Calc'd for C₉H₉NO,148; Found, 148.

Preparation 135b: Tert-ButylN-{[(1R)-6-[(1-benzofuran-6-yl)(methyl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}carbamate

The title compound was prepared in 61% yield from Preparation 6d andPreparation 135a according to the general procedure outlined forPreparation 6e. [M+H] Calc'd for C₂₅H₃₀N₂O, 407; Found, 407.

Preparation 135c:N-[(5R)-5-(aminomethyl)-5,6,7,8-tetrahydronaphthalen-2-yl]-N-methyl-1-benzofuran-6-amine

The title compound was prepared in 95% yield from Preparation 135baccording to the procedure for Preparation 43b. [M+H] Calc'd forC₂₀H₂₂N₂O, 307; Found, 307.

Preparation 135d: Methyl3-({[(1R)-6-[(1-benzofuran-6-yl)(methyl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 50% yield from Preparation 135caccording to the procedure for Preparation 4d. [M+H] Calc'd forC₂₇H₂₇N₃O₃, 442; Found, 442.

Example 135:3-({[(1R)-6-[(1-benzofuran-6-yl)(methyl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 43% yield from Preparation 135daccording to the procedure for Example 1. ¹H NMR (400 MHz, MeOD-d₄): δ1.73-1.96 (4H, m), 2.69-2.76 (2H, m), 3.11-3.16 (1H, m), 3.28 (3H, s),3.36-3.60 (2H, m), 6.10 (1H, s), 6.73-6.79 (3H, m), 6.90 (1H, d, J=8.4Hz), 7.08 (1H, s), 7.16 (1H, d, J=8.2 Hz), 7.42 (1H, d, J=8.4 Hz), 7.62(1H, s), 7.78-7.83 (2H, m), 8.15 (1H, s). [M+H] Calc'd for C₂₆H₂₆N₃O₃,428; Found, 428.

Preparation 136a: N-methyl-1-benzofuran-5-amine

The title compound was prepared in 76% overall yield from1-benzofuran-5-amine according to the general procedure outlined forPreparation 127a. [M+H] Calc'd for C₉H₉NO, 148; Found, 148.

Preparation 136b: Tert-ButylN-{[(4R)-7-[(1-benzofuran-5-yl)(methyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}carbamate

The title compound was prepared in 14% yield from Preparation 18d andPreparation 136a according to the general procedure outlined forPreparation 6e. [M+H] Calc'd for C₂₄H₂₈N₂O₄, 409; Found, 409.

Preparation 136c:(4R)-4-(aminomethyl)-N-(1-benzofuran-5-yl)-N-methyl-3,4-dihydro-2H-1-benzopyran-7-amine

The title compound was prepared in 75% yield from Preparation 136baccording to the procedure for Preparation 43b. [M+H] Calc'd forC₁₉H₂₀N₂O₂, 309; Found, 309.

Preparation 136d: Methyl3-({[(4R)-7-[(1-benzofuran-5-yl)(methyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 53% yield from Preparation 136caccording to the procedure for Preparation 4d. [M+H] Calc'd forC₂₆H₂₅N₃O₄, 444; Found, 444.

Example 136:3-({[(4R)-7-[(1-benzofuran-5-yl)(methyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 50% yield from Preparation 136daccording to the procedure for Example 1. ¹H NMR (400 MHz, MeOD-d₄): δ1.83-1.88 (1H, m), 1.99-2.09 (1H, m), 3.03-3.06 (1H, m), 3.14 (3H, s),3.41-3.47 (1H, m), 3.55-3.60 (1H, m), 4.02-4.14 (2H, m), 6.10 (1H, s),6.17 (1H, d, J=5.6 Hz), 6.69 (1H, s), 6.90-6.95 (2H, m), 7.25 (1H, s),7.34 (1H, d, J=8.4 Hz), 7.63 (1H, s), 7.81 (1H, s), 8.13 (1H, d, J=5.6Hz), 8.22 (1H, s). [M+H] Calc'd for C₂₅H₂₃N₃O₄, 430; Found, 430.

Preparation 137a: Methyl3-({[(1R)-6-[(1-benzofuran-5-yl)(methyl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 15% yield from Preparation 122a andPreparation 136a according to the general procedure outlined forPreparation 126c. [M+H] Calc'd for C₂₇H₂₇N₃O₃, 442; Found, 442.

Example 137:3-({[(1R)-6-[(1-benzofuran-5-yl)(methyl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 23% yield from Preparation 137aaccording to the procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ1.76-1.79 (1H, m), 1.86-2.06 (3H, m), 2.70-2.75 (2H, m), 3.13-3.17 (1H,m), 3.28 (3H, s), 3.51-3.63 (2H, m), 6.60 (2H, s), 6.80 (1H, s),7.02-7.09 (2H, m), 7.33 (1H, s), 7.44 (1H, d, J=8.4 Hz), 7.90 (1H, s),7.75 (1H, s), 8.18 (1H, d, J=2.0 Hz), 8.26 (1H, s). [M+H] Calc'd forC₂₆H₂₅N₃O₃, 428; Found, 428.

Preparation 138a: Methyl3-({[(4R)-7-(2-hydroxyphenyl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

To a solution of Preparation 126b (180 mg, 0.48 mmol) in DMF (5 mL) wasadded 2-hydroxyphenylboronic acid (80 mg, 0.57 mmol), K₂CO₃ (133 mg,0.96 mmol) and Pd(PPh₃)₄ (58 mg, 0.05 mmol). The mixture was stirred for4 h at 105° C. under nitrogen. The mixture was cooled, diluted withwater, and extracted with EtOAc. Organics were washed with brine, dried(Na₂SO₄), and concentrated to give 147 mg (79%) of the title compound asa yellow solid. [M+H] Calc'd for C₂₃H₂₂N₂O₄, 391; Found, 391.

Example 138:3-({[(4R)-7-(2-hydroxyphenyl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 40% yield from Preparation 138aaccording to the procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ1.92-1.93 (1H, m), 1.98-2.03 (1H, m), 3.14-3.17 (1H, m), 3.50-3.56 (1H,m), 3.71-3.75 (1H, m), 4.17-4.23 (2H, m), 6.82-7.22 (6H, m), 7.31 (1H,d, J=8.0 Hz), 7.57 (1H, d, J=4.8 Hz), 7.85 (1H, d, J=5.2 Hz), 8.44 (1H,s), 9.44 (1H, s).

[M+H] Calc'd for C₂₂H₂₀N₂O₄, 377; Found, 377.

Preparation 139a: Tert-ButylN-{[(1R)-6-(methylamino)-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}carbamate

Preparation 6d (300 mg, 0.88 mmol), CuI (201 mg, 1.06 mmol), KOAc (216mg, 2.2 mmol), and CuOAc (176 mg, 0.88 mmol) were combined in DMF (3 mL)in a microwave tube. Methylamine (0.7 mL, 40% in water, 8.8 mmol) wasadded, and the reaction stirred at 100° C. in the microwave for 2 h. Thereaction was diluted with EtOAc, washed with water and brine, dried(MgSO₄), and concentrated. The residue was purified by silica gelchromatography (20% to 80% EtOAc/hexanes) to give 186 mg (73%) of thetitle compound as a yellow oil. [M+H] Calc'd for C₁₇H₂₆N₂O₂, 291; Found,291.

Preparation 139b: Tert-ButylN-{[(1R)-6-[methyl(2-methyl-1,3-thiazol-4-yl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}carbamate

To a suspension of Preparation 139a (200 mg, 0.69 mmol),4-bromo-2-methyl-1,3-thiazole (184 mg, 1.03 mmol), Xantphos (60 mg, 0.10mmol) and Cs₂CO₃ (315 mg, 0.97 mmol) in toluene (20 mL) was addedPd₂dba₃ (32 mg, 0.04 mmol) at r.t. under N₂. The reaction was stirred atreflux overnight. The reaction was cooled, filtered, and concentrated.The residue was purified by silica gel chromatography (PE:EtOAc=3:1) togive 60 mg (23%) of the title compound as a yellow oil. [M+H] Calc'd forC₂₁H₂₉N₃O₂S, 388; Found, 388.

Preparation 139c:N-[(5R)-5-(aminomethyl)-5,6,7,8-tetrahydronaphthalen-2-yl]-N,2-dimethyl-1,3-thiazol-4-amine

The title compound was prepared in quantitative yield from Preparation136b according to the procedure for Preparation 43b. [M+H] Calc'd forC₁₆H₂₁N₃S, 288; Found, 288.

Preparation 139d: Methyl3-({[(1R)-6-[methyl(2-methyl-1,3-thiazol-4-yl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 23% yield from Preparation 139caccording to the procedure for Preparation 4d. [M+H] Calc'd forC₂₃H₂₆N₄O₂S, 423; Found, 423.

Example 139:3-({[(1R)-6-[methyl(2-methyl-1,3-thiazol-4-yl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 63% yield from Preparation 139daccording to the procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ1.651.69 (1H, m), 1.81-1.85 (3H, m), 2.57 (3H, s), 2.67-2.70 (2H, m),3.05-3.07 (1H, m), 3.25 (3H, s), 3.42-3.45 (1H, m), 3.55-3.60 (1H, m),6.32 (1H, s), 6.84 (1H, d, J=2.8 Hz), 6.90 (1H, dd, J=2.4, 8.4 Hz), 7.21(1H, d, J=8.4 Hz), 7.56 (1H, d, J=4.4 Hz), 7.83 (1H, d, J=5.2 Hz), 8.36(1H, s). [M+H] Calc'd for C₂₂H₂₄N₄O₂S, 409; Found, 409.

Preparation 140a: Tert-ButylN-{[(1R)-6-[methyl(4-methylphenyl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}carbamate

The title compound was prepared in 38% yield from Preparation 6d andN,4-dimethylaniline according to the general procedure outlined forPreparation 9a. [M+H] Calc'd for C₂₆H₃₂N₂O₂, 381; Found, 381.

Preparation 140b:(5R)-5-(aminomethyl)-N-methyl-N-(4-methylphenyl)-5,6,7,8-tetrahydronaphthalen-2-amine

The title compound was prepared in quantitative yield from Preparation140a according to the procedure for Preparation 43b. [M+H] Calc'd forC₁₉H₂₄N₂, 281; Found, 281.

Preparation 140c: Methyl3-({[(1R)-6-[methyl(4-methylphenyl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 76% yield from Preparation 140baccording to the procedure for Preparation 4d. [M+H] Calc'd forC₂₆H₂₉N₃O₂, 416; Found, 416.

Example 140:3-({[(1R)-6-[methyl(4-methylphenyl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 98% yield from Preparation 140caccording to the procedure for Example 1. ¹H NMR (300 MHz, DMSO-d₆): δ1.63-1.81 (4H, m), 2.24 (3H, s), 2.64-2.65 (2H, m), 2.99-3.05 (1H, m),3.18 (3H, s), 3.38-3.42 (1H, m), 3.53-3.59 (1H, m), 6.66-6.71 (2H, m),6.88-6.90 (2H, m), 7.09 (2H, d, J=2.4 Hz), 7.17 (1H, d, J=8.1 Hz), 7.55(1H, d, J=5.1 Hz), 7.82 (1H, d, J=5.1 Hz), 8.34 (1H, s). [M+H] Calc'dfor C₂₅H₂₇N₃O₂, 402; Found, 402.

Preparation 141a: Methyl3-({[(4R)-7-[(1-benzofuran-6-yl)(methyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

To a solution of Preparation 135a (250 mg, 1.71 mmol) in toluene (10 mL)was added Preparation 126b (536 mg, 1.42 mmol), Cs₂CO₃ (926 mg, 2.84mmol), BINAP (44 mg, 0.07 mmol) and Pd(OAc)₂ (16 mg, 0.07 mmol). Themixture was stirred overnight at 120° C. under nitrogen. The mixture wasfiltered and concentrated. The residue was purified by silica gelchromatography to give 160 mg (25%) of the title compound as a whitesolid. [M+H] Calc'd for C₂₆H₂₅N₃O₄, 444; Found, 444.

Example 141:3-({[(4R)-7-[(1-benzofuran-6-yl)(methyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 40% yield from Preparation 141aaccording to the procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ1.83-1.87 (1H, m), 1.96-2.00 (1H, m), 3.05-3.08 (1H, m), 3.24 (3H, s),3.46-3.51 (1H, m), 3.64-3.69 (1H, m), 4.10-4.20 (2H, m), 6.33 (1H, s),6.45 (1H, d, J=6.0 Hz), 6.88 (1H, s), 6.94 (1H, d, J=6.8 Hz), 7.15 (1H,d, J=8.4 Hz), 7.25 (1H, s), 7.51 (1H, d, J=8.8 Hz), 7.62 (1H, d, J=4.8Hz), 7.86-7.89 (2H, m), 8.41 (1H, s). [M+H] Calc'd for C₂₅H₂₃N₃O₄, 430;Found, 430.

Preparation 142a: Methyl3-[(3,4-dihydro-1H-2-benzopyran-1-ylmethyl)amino]pyridine-4-carboxylate

The title compound was prepared in 70% yield from3,4-dihydro-1H-2-benzopyran-1-ylmethanamine according to the procedurefor Preparation 4d. ¹H NMR (400 MHz, CDCl₃): δ 2.72-2.78 (1H, m),3.00-3.09 (1H, m), 3.53-3.60 (1H, m), 3.78-3.87 (5H, m), 4.18-4.24 (1H,m), 5.07 (1H, d, J=6.4 Hz), 7.15-7.22 (4H, m), 7.60 (1H, d, J=5.0 Hz),7.72 (1H, br s), 7.91 (1H, d, J=5.0 Hz), 8.31 (1H, s). [M+H] Calc'd forC₁₇H₁₈N₂O₃, 299; Found, 299.

Example 142:3-[(3,4-dihydro-1H-2-benzopyran-1-ylmethyl)amino]pyridine-4-carboxylicAcid

The title compound was prepared in 53% yield from Preparation 142aaccording to the procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ2.69-2.74 (1H, m), 2.86-2.94 (1H, m), 3.54-3.60 (1H, m), 3.71-3.85 (2H,m), 4.08-4.12 (1H, m), 4.98 (1H, d, J=5.8 Hz), 7.16-7.21 (3H, m), 7.34(1H, d, J=4.2 Hz), 7.52 (1H, d, J=4.8 Hz), 7.81 (1H, d, J=4.8 Hz), 7.90(1H, br s), 8.34 (1H, s), 12.52 (1H, br s). [M+H] Calc'd for C₁₆H₁₆N₂O₃,285; Found, 285.

Example 143:3-({[(1R)-6-[methyl(3-methylphenyl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylicAcid

To a solution of Preparation 122a (374 mg, 1.0 mmol) in toluene (10 mL)was added N,3-dimethylaniline (242 mg, 2.0 mmol), t-BuONa (192 mg, 2.0mmol), JohnPhos (45 mg, 0.15 mmol) and Pd₂(dba)₃ (92 mg, 0.1 mmol). Themixture was refluxed for 3 h under N₂. The reaction was cooled, filteredand concentrated. The residue was purified by prep-HPLC to give 21 mg(5%) of the title compound as a yellow solid. (Ester hydrolysis occurredduring the course of the reaction.) ¹H NMR (300 MHz, MeOD-d₄): δ1.76-1.80 (1H, m), 1.83-2.02 (3H, m), 2.26 (3H, s), 2.71-2.75 (2H, m),3.15-3.19 (1H, m), 3.22 (3H, s), 3.56-3.60 (2H, m), 6.73-6.78 (5H, m),7.08-7.16 (2H, m), 7.89-7.91 (1H, m), 8.21 (1H, d, J=5.4 Hz), 8.29 (1H,s). [M+H] Calc'd for C₂₅H₂₇N₃O₂, 402; Found, 402.

Preparation 144a: Tert-ButylN-{[(1R)-6-[methyl(thiophen-2-yl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}carbamate

To a suspension of Preparation 139a (50 mg, 0.17 mmol),2-bromo-thiophene (56 mg, 0.34 mmol), JohnPhos (8 mg, 0.03 mmol) andt-BuONa (33 mg, 0.34 mmol) in toluene (10 mL) was added Pd₂dba₃ (16 mg,0.02 mmol) at r.t. under N₂. The reaction was stirred at refluxovernight. The reaction was cooled, filtered, and concentrated. Theresidue was purified by silica gel chromatography (PE:EtOAc=8:1) to give40 mg (63%) of the title compound as a yellow oil.

[M+H] Calc'd for C₂₁H₂₈N₂O₂S, 373; Found, 373.

Preparation 144b:N-[(5R)-5-(aminomethyl)-5,6,7,8-tetrahydronaphthalen-2-yl]-N-methylthiophen-2-amine

The title compound was prepared in quantitative yield from Preparation144a according to the procedure for Preparation 43b. [M+H] Calc'd forC₁₆H₂₀N₂S, 273; Found, 273.

Preparation 144c: Methyl3-({[(1R)-6-[methyl(thiophen-2-yl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 22% yield from Preparation 144baccording to the procedure for Preparation 4d. [M+H] Calc'd forC₂₃H₂₅N₃O₂S, 408; Found, 408.

Example 144:3-({[(1R)-6-[methyl(thiophen-2-yl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 53% yield from Preparation 144caccording to the procedure for Example 1. ¹H NMR (300 MHz, DMSO-d₆): δ1.59-1.64 (1H, m), 1.76-1.84 (3H, m), 2.65-2.69 (2H, m), 2.98-3.05 (1H,m), 3.23 (3H, s), 3.41-3.43 (1H, m), 3.51-3.57 (1H, m), 6.59 (1H, d,J=2.7 Hz), 6.75-6.78 (2H, m), 6.88 (1H, dd, J=3.9, 5.1 Hz), 7.03 (1H,dd, J=0.6, 5.1 Hz), 7.19 (1H, d, J=8.1 Hz), 7.55 (1H, d, J=4.2 Hz), 7.83(1H, d, J=4.5 Hz), 8.34 (1H, s). [M+H] Calc'd for C₂₂H₂₃N₃O₂S, 394;Found, 394.

Preparation 145a: Tert-ButylN-{[(4R)-7-[methyl(5-methylpyridin-2-yl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}carbamate

The title compound was prepared in 9% yield from Preparation 18d andN,5-dimethylpyridin-2-amine according to the general procedure outlinedfor Preparation 6e. [M+H] Calc'd for C₂₂H₂₉N₃O₃, 384; Found, 384.

Preparation 145b:N-[(4R)-4-(aminomethyl)-3,4-dihydro-2H-1-benzopyran-7-yl]-N,5-dimethylpyridin-2-amine

The title compound was prepared in quantitative yield from Preparation145a according to the procedure for Preparation 43b. [M+H] Calc'd forC₁₇H₂₁N₃O, 284; Found, 284.

Preparation 145c: Methyl3-({[(4R)-7-[methyl(5-methylpyridin-2-yl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 78% yield from Preparation 145baccording to the procedure for Preparation 4d. [M+H] Calc'd forC₂₄H₂₆N₄O₃, 419; Found, 419.

Example 145:3-({[(4R)-7-[methyl(5-methylpyridin-2-yl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 65% yield from Preparation 145caccording to the procedure for Example 1. ¹H NMR (300 MHz, DMSO-d₆): δ1.88-1.91 (1H, m), 1.96-2.03 (1H, m), 2.14 (3H, s), 3.10-3.14 (1H, m),3.25 (3H, s), 3.43-3.55 (1H, m), 3.68-3.74 (1H, m), 4.13-4.21 (2H, m),6.52 (1H, d, J=8.4 Hz), 6.63 (1H, s), 6.72 (1H, d, J=8.1 Hz), 7.26-7.32(2H, m), 7.56 (1H, d, J=5.1 Hz), 7.84 (1H, d, J=6.9 Hz), 7.98 (1H, s),8.41 (1H, s). [M+H] Calc'd for C₂₃H₂₄N₄O₃, 405; Found, 405.

Preparation 146a: 2-{3-[methyl(phenyl)amino]phenyl}ethan-1-ol

1-Bromo-3-[2-(tert-butyldimethylsilyloxy)ethyl]benzene (2.5 g, 7.96mmol), N-methylaniline (1.02 g, 9.55 mmol), Pd₂dba₃ (364 mg, 0.4 mmol),Xantphos (691 mg, 1.19 mmol) and NaOtBu (727 mg, 9.55 mmol) werecombined in toluene (12 mL), and the reaction was heated at 100° C. inthe microwave for 90 min. The reaction was diluted with EtOAc, washedwith brine, dried (MgSO₄), and concentrated. The residue was stirred in70% TFA/DCM (10 mL) for 2 h. The solution was concentrated and purifiedby silica gel chromatography (30% to 100% EtOAc/hexanes) to give 1.3 g(72%) of the title compound as a clear oil. ¹H NMR (400 MHz, CDCl₃): δ1.53 (1H, br s), 2.81 (2H, t, J=6.5 Hz), 3.31 (3H, s), 3.83 (2H, t,J=6.5 Hz), 6.81 (1H, d, J=7.4 Hz), 6.86-6.89 (2H, m), 6.97 (1H, t, J=7.3Hz), 7.04 (d, 2H, J=7.8 Hz), 7.18-7.29 (3H, m). [M+H] Calc'd forC₁₅H₁₇NO, 228; Found, 228.

Preparation 146b:1-(aminomethyl)-N-methyl-N-phenyl-3,4-dihydro-1H-2-benzopyran-6-amine

2-{3-[Methyl(phenyl)amino]phenyl}ethan-1-ol (1.0 g, 4.4 mmol) wasstirred in 4N HCl/dioxane (8 mL) at 0° C. Aminoacetaldehyde diethylacetal (880 mg, 6.6 mmol) was added, and the reaction stirred for atr.t. for 1 h and then at 108° C. in the microwave for 1 h. The solutionwas concentrated and purified by silica gel chromatography (0% to 20%MeOH/DCM) to give 150 mg (13%) of the title compound as a yellow oil.[M+H] Calc'd for C₁₇H₂₀N₂O, 269; Found, 269.

Example 146:3-[({6-[methyl(phenyl)amino]-3,4-dihydro-1H-2-benzopyran-1-yl}methyl)amino]pyridine-4-carboxylicAcid

3-Flouroisonicotinic acid (79 mg, 0.56 mmol), Preparation 146b (150 mg,0.56 mmol), and DIEA (0.098 mL, 0.56 mmol) were combined in DMA (4 mL)and heated at 168° C. in the microwave for 1 h. The solution wasconcentrated, and the residue was purified by prep-HPLC to give 18 mg(8%) of the title compound as a tan solid. ¹H NMR (400 MHz, DMSO-d₆): δ2.60-2.83 (1H, m), 2.79-2.86 (1H, m), 3.23 (3H, s), 3.53-3.59 (1H, m),3.70-3.82 (2H, m), 4.04-4.10 (1H, m), 4.90-4.96 (1H, m), 6.78-6.98 (5H,m), 7.22-7.28 (3H, m), 7.53 (1H, d, J=4.8 Hz), 7.74 (1H, br s), 7.81(1H, d, J=4.8 Hz), 8.36 (1H, s), 13.25 (1H, br s). [M+H] Calc'd forC₂₃H₂₃N₃O₃, 390; Found, 390.

Preparation 147a: N-{2-[(tert-butyldimethylsilyl)oxy]ethyl}aniline

To a solution of 2-(phenylamino)ethan-1-ol (2.0 g, 14.6 mmol) andimidazole (2.9 g, 43.7 mmol) in DCM (20 mL) was added TBSCl (2.6 g, 16.0mmol) at r.t., and the reaction was stirred for 2 h. The reaction wasdiluted with water (50 mL) and extracted with DCM (50 mL×3). Organicswere washed with brine (50 mL), dried (Na₂SO₄), and concentrated.Purification by silica gel chromatography (PE:EtOAc=40:1) gave 3.0 g(82%) of the title compound as a yellow oil.

Preparation 147b: methyl3-({[(1R)-6-({2-[(tert-butyldimethylsilyl)oxy]ethyl}(phenyl)amino)-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 28% yield from Preparation 122a andN-{2-[(tert-butyldimethylsilyl)oxy]ethyl}aniline according to thegeneral procedure outlined for Preparation 126c. [M+H] Calc'd forC₃₂H₄₃N₃O₃Si, 546; Found, 546.

Example 147:3-({[(1R)-6-[(2-hydroxyethyl)(phenyl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylicAcid

To a solution of Preparation 147b (80 mg, 0.15 mmol) in THF (5 mL) wasadded TBAF (0.29 mL, 1.0 M in THF, 0.29 mmol) at r.t., and the reactionwas stirred for 1 h. To the reaction mixture was added H₂O (5 mL) andLiOH.H₂O (13 mg, 0.30 mmol). The reaction was stirred at r.t. for 2 h.The solution was concentrated to remove THF, and the residue wasacidified to pH=5 with 1.0 N aqueous HCl solution. The solid wascollected by filtration and then purified by prep-HPLC to give compound30 mg (48%) of the title compound as a yellow solid. ¹H NMR (300 MHz,DMSO-d₆): δ 1.65-1.68 (1H, m), 1.74-1.84 (3H, m), 2.62-2.67 (2H, m),3.04-3.07 (1H, m), 3.41-3.46 (1H, m), 3.54-3.60 (3H, m), 3.72 (2H, d,J=4.8 Hz), 4.73 (1H, br s), 6.80-6.93 (3H, m), 6.92 (2H, d, J=5.7 Hz),7.19-7.24 (3H, m), 7.55 (1H, d, J=3.9 Hz), 7.83 (1H, d, J=3.6 Hz), 8.36(1H, s). [M+H] Calc'd for C₂₅H₂₇N₃O₃, 418; Found, 418.

Preparation 148a: Tert-ButylN-{[(4R)-7-[methyl(6-methylpyridin-2-yl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}carbamate

The title compound was prepared in 27% yield from Preparation 18d andN,6-dimethylpyridin-2-amine according to the general procedure outlinedfor Preparation 6e. [M+H] Calc'd for C₂₂H₂₉N₃O₃, 384; Found, 384.

Preparation 148b:N-[(4R)-4-(aminomethyl)-3,4-dihydro-2H-1-benzopyran-7-yl]-N,6-dimethylpyridin-2-amine

The title compound was prepared in quantitative yield from Preparation148a according to the procedure for Preparation 43b. [M+H] Calc'd forC₁₇H₂₁N₃O, 284; Found, 284.

Preparation 148c: Methyl3-({[(4R)-7-[methyl(6-methylpyridin-2-yl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 77% yield from Preparation 148baccording to the procedure for Preparation 4d. [M+H] Calc'd forC₂₄H₂₆N₄O₃, 419; Found, 419.

Example 148:3-({[(4R)-7-[methyl(6-methylpyridin-2-yl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 78% yield from Preparation 148caccording to the procedure for Example 1. ¹H NMR (300 MHz, DMSO-d₆): δ1.88-2.01 (2H, m), 2.32 (3H, s), 3.09-3.16 (1H, m), 3.32 (3H, s),3.46-3.54 (1H, m), 3.67-3.73 (1H, m), 4.13-4.21 (2H, m), 6.31 (1H, d,J=8.4 Hz), 6.50 (1H, d, J=7.2 Hz), 6.64 (1H, d, J=2.4 Hz), 6.72-6.75(1H, m), 7.25-7.33 (2H, m), 7.55 (1H, d, J=5.1 Hz), 7.83 (1H, d, J=4.8Hz), 8.39 (1H, s). [M+H] Calc'd for C₂₃H₂₄N₄O₃, 405; Found, 405.

Preparation 149a: Tert-Butyl1-(aminomethyl)-1,2,3,4-tetrahydroisoquinoline-2-carboxylate

Methanesulfonyl chloride (0.324 mL, 4.18 mmol) was added to a solutionof tert-butyl1-(hydroxymethyl)-1,2,3,4-tetrahydroisoquinoline-2-carboxylate (1.0 g,3.8 mmol) and DIEA (0.812 mL, 4.56 mmol) in DCM (20 mL) at r.t., and thesolution was stirred overnight. The solution was washed with brine,dried (MgSO₄), and concentrated to give the crude mesylate intermediate.

This mesylate intermediate was stirred in DMF (8 mL) with sodium azide(1.5 g, 22.8 mmol) at 52° C. overnight. The reaction was diluted withEtOAc (30 mL), filtered, and concentrated. The residue was dissolved inMeOH (30 mL) and hydrogenated under a balloon of H₂ in the presence of10% Pd/C overnight. The reaction was filtered through Celite andconcentrated. Purification by silica gel chromatography (0% to 20%MeOH/DCM) gave 250 mg (25%) of the title compound as a clear oil. [M+H]Calc'd for C₁₅H₂₂N₂O₂, 263; Found, 263.

Example 149:3-[(1,2,3,4-tetrahydroisoquinolin-1-ylmethyl)amino]pyridine-4-carboxylicAcid

3-Flouroisonicotinic acid (135 mg, 0.95 mmol), Preparation 149a (250 mg,0.95 mmol), and DIEA (0.17 mL, 0.95 mmol) were combined in DMA (4 mL)and heated at 168° C. in the microwave for 1 h. The solution wasconcentrated, and then the residue stirred in 50% TFA/DCM (4 mL) for 1h. The solution was concentrated, and the residue was purified byprep-HPLC to give 28 mg (7%) of the title compound as a pale yellowsolid. ¹H NMR (400 MHz, DMSO-d₆): δ 3.00-3.05 (2H, m), 3.28-3.33 (1H,m), 3.54-3.60 (1H, m), 3.80-3.86 (1H, m), 4.05-4.09 (1H, m), 4.87 (1H,br s), 7.26-7.35 (3H, m), 7.50 (1H, d, J=6.2 Hz), 7.71 (1H, d, J=5.0Hz), 7.80-7.85 (1H, m), 7.99 (1H, d, J=4.8 Hz), 8.55 (1H, s), 8.90 (1H,br s), 9.40 (1H, br s). [M+H] Calc'd for C₁₆H₁₇N₃O₂, 284; Found, 284.

Preparation 150a: methyl3-({[(1R)-6-[(3-methoxyphenyl)(methyl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 43% yield from Preparation 122a and3-fluoro-N,4-dimethylaniline according to the general procedure outlinedfor Preparation 126c. [M+H] Calc'd for C₂₆H₂₉N₃O₃, 432; Found, 432.

Example 150:3-({[(1R)-6-[(3-methoxyphenyl)(methyl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 92% yield from Preparation 150aaccording to the procedure for Example 1. ¹H NMR (300 MHz, DMSO-d₆): δ1.64-1.67 (1H, m), 1.76-1.83 (3H, m), 2.65-2.67 (2H, m), 3.01-3.06 (1H,m), 3.19 (3H, s), 3.41-3.44 (1H, m), 3.53-3.59 (1H, m), 3.67 (3H, s),6.40-6.45 (3H, m), 6.80-6.84 (2H, m), 7.09 (1H, t, J=8.1 Hz), 7.24 (1H,d, J=8.4 Hz), 7.54 (1H, d, J=4.5 Hz), 7.80 (1H, d, J=3.9 Hz), 8.32 (1H,s). [M+H] Calc'd for C₂₅H₂₇N₃O₃, 418; Found, 418.

Preparation 151a: 3-fluoro-N,4-dimethylaniline

To a suspension of 4-bromo-2-fluoro-1-methylbenzene (1.0 g, 5.3 mmol),KOAc (1.3 g, 13.2 mmol), and CuI (1.2 g, 6.4 mmol) in DMF (20 mL) wasadded methylamine (26.5 mL, 2.0M in THF, 53.0 mmol) at r.t. under N₂.The reaction was stirred at 100° C. overnight in a sealed tube. Thereaction mixture was filtered, diluted with water (50 mL), and extractedwith EtOAc (50 mL×3). The organic layers were washed with ammoniumhydroxide (50 mL×3) and brine (50 mL), dried (Na₂SO₄), and concentrated.The residue was purified by silica gel chromatography (PE:EtOAc=20:1) togive 310 mg (42%) of the title compound as a yellow oil. [M+H] Calc'dfor C₈H₁₀FN, 140; Found, 140.

Preparation 151b: Methyl3-({[(4R)-7-[(3-fluoro-4-methylphenyl)(methyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 58% yield from Preparation 126b and3-fluoro-N,4-dimethylaniline according to the general procedure outlinedfor Preparation 126c. [M+H] Calc'd for C₂₅H₂₆FN₃O₃, 436; Found, 436.

Example 151:3-({[(4R)-7-[(3-fluoro-4-methylphenyl)(methyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 93% yield from Preparation 151baccording to the procedure for Example 1. ¹H NMR (300 MHz, DMSO-d₆): δ1.83-1.89 (1H, m), 1.93-1.98 (1H, m), 2.12 (3H, s), 3.04-3.08 (1H, m),3.16 (3H, s), 3.42-3.49 (1H, m), 3.63-3.69 (1H, m), 4.09-4.18 (2H, m),6.41 (1H, d, J=2.4 Hz), 6.53 (1H, dd, J=2.4, 8.4 Hz), 6.62-6.70 (2H, m),7.06-7.12 (1H, m), 7.21 (1H, d, J=8.4 Hz), 7.55 (1H, d, J=5.1 Hz), 7.81(1H, d, J=5.1 Hz), 8.37 (1H, s). [M+H] Calc'd for C₂₄H₂₄FN₃O₃, 422;Found, 422.

Preparation 152a: Tert-ButylN-{[(4R)-7-(methylamino)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}carbamate

To a suspension of Preparation 18d (1.00 g, 2.91 mmol), KOAc (710 mg,7.25 mmol), methylamine (15 mL, 2 M in THF) in DMF (30 mL) was added CuI(663 mg, 3.49 mmol) at r.t. under N₂. The reaction was sealed andstirred at 100° C. overnight. The reaction was diluted with EtOAc,filtered, and washed with sat NaHCO₃ (10 mL). The organic layer wasconcentrated, and the residue was purified by silica gel chromatography(PE:EtOAc=5:1) to give 286 mg (34%) of the title compound as a yellowsolid. [M+H] Calc'd for C₁₆H₂₄N₂O₃, 293; Found, 293.

Preparation 152b: Tert-ButylN-{[(4R)-7-[(5-chloropyridin-2-yl)(methyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}carbamate

To a suspension of Preparation 152a (116 mg, 0.40 mmol),5-bromo-2-chloropyridine (153 mg, 0.80 mmol), S-phos (24 mg, 0.06 mmol)and Cs₂CO₃ (182 mg, 0.56 mmol) in toluene (20 mL) was added Pd₂dba₃ (36mg, 0.04 mmol) at r.t. under N₂. The reaction was stirred at 120° C.overnight. The reaction was filtered and concentrated. The residue waspurified by silica gel chromatography (PE:EtOAc=5:1) to give 63 mg (39%)of the title compound as a yellow solid. [M+H] Calc'd for C₂₁H₂₆ClN₃O₃,404; Found, 404.

Preparation 152c:N-[(4R)-4-(aminomethyl)-3,4-dihydro-2H-1-benzopyran-7-yl]-5-chloro-N-methylpyridin-2-amine

The title compound was prepared in 97% yield from Preparation 152baccording to the procedure for Preparation 43b. [M+H] Calc'd forC₁₆H₁₈ClN₃O, 304; Found, 304.

Preparation 152d: methyl3-({[(4R)-7-[(5-chloropyridin-2-yl)(methyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 47% yield from Preparation 152caccording to the procedure for Preparation 4d. [M+H] Calc'd forC₂₃H₂₃ClN₄O₃, 439; Found, 439.

Example 152:3-({[(4R)-7-[(5-chloropyridin-2-yl)(methyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 70% yield from Preparation 152daccording to the procedure for Example 1. ¹H NMR (300 MHz, DMSO-d₆): δ1.88-2.21 (2H, m), 3.15-3.25 (1H, m), 3.33 (3H, s), 3.49-3.56 (1H, m),3.71-3.74 (1H, m), 4.20-4.24 (2H, m), 6.52 (1H, d, J=9.3 Hz), 6.71 (1H,s), 6.78 (1H, dd, J=7.8 Hz), 7.38 (1H, d, J=6.6 Hz), 7.50 (1H, d, J=9.3Hz), 7.58 (1H, d, J=3.0 Hz), 7.85 (1H, dd, J=4.5, 1.5 Hz), 8.15 (1H, s),8.41 (1H, s). [M+H] Calc'd for C₂₂H₂₁ClN₄O₃, 425; Found, 425.

Preparation 153a: 2-chloro-5-cyclopropylpyridine

To a suspension of 5-bromo-2-chloropyridine (990 mg, 5.15 mmol),cyclopropylboronic acid (893 mg, 10.39 mmol) and Cs₂CO₃ (5.082 g, 15.45mmol) in 1,4-dioxane (25 mL) was added Pd(PPh₃)₄ (601 mg, 0.52 mmol) atr.t. under N₂. The reaction was stirred at 100° C. for 1 h. Afterfiltration, the solvent was removed in vacuo, and the residue waspurified by silica gel chromatography (PE:EtOAc=50:1) to give 452 mg(57%) of the title compound as a colorless oil. [M+H] Calc'd forC₈H₈NCl, 154; Found, 154.

Preparation 153b: Tert-ButylN-{[(4R)-7-[(5-cyclopropylpyridin-2-yl)(methyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}carbamate

To a suspension of 2-chloro-5-cyclopropylpyridine (333 mg, 2.18 mmol),Preparation 152a (317 mg, 1.09 mmol), S-phos (70 mg, 0.17 mmol) andCs₂CO₃ (499 mg, 1.53 mmol) in toluene (20 mL) was added Pd₂dba₃ (101 mg,0.11 mmol) at r.t. under N₂. The reaction was stirred at 120° C.overnight. After filtration, the solvent was removed in vacuo, and theresidue was purified by silica gel chromatography (PE:EtOAc=10:1) togive 330 mg (75%) of the title compound as a yellow oil. [M+H] Calc'dfor C₂₄H₃₁N₃O₃, 410; Found, 410.

Preparation 153c:N-[(4R)-4-(aminomethyl)-3,4-dihydro-2H-1-benzopyran-7-yl]-5-cyclopropyl-N-methylpyridin-2-amine

The title compound was prepared in 94% yield from Preparation 153baccording to the procedure for Preparation 43b. [M+H] Calc'd forC₁₉H₂₃N₃O, 310; Found, 310.

Preparation 153d: Methyl3-({[(4R)-7-[(5-cyclopropylpyridin-2-yl)(methyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 86% yield from Preparation 153daccording to the procedure for Preparation 4d. [M+H] Calc'd forC₂₆H₂₈N₄O₃, 445; Found, 445.

Example 153:3-({[(4R)-7-[(5-cyclopropylpyridin-2-yl)(methyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 39% yield from Preparation 153daccording to the procedure for Example 1. ¹H NMR (300 MHz, DMSO-d₆): δ0.55-0.59 (2H, m), 0.83-0.89 (2H, m), 1.78-2.02 (3H, m), 3.12-3.15 (1H,m), 3.31 (3H, s), 3.48-3.55 (1H, m), 3.72 (1H, dd, J=4.2, 13.5 Hz),4.14-4.22 (2H, m), 6.53 (1H, d, J=8.4 Hz), 6.63 (1H, s), 6.74-6.71 (1H,m), 7.12 (1H, dd, J=2.1, 8.4 Hz), 7.31 (1H, d, J=8.4 Hz), 7.57 (1H, d,J=4.8 Hz), 7.85 (1H, d, J=5.1 Hz), 8.00 (1H, s), 8.41 (1H, s). [M+H]Calc'd for C₂₅H₂₆N₄O₃, 431; Found, 431.

Preparation 154a: 4-ethyl-N-methylaniline

The title compound was prepared in 60% overall yield from 4-ethylanilineaccording to the general procedure outlined for Preparation 127a. [M+H]Calc'd for C₉H₁₃N, 136; Found, 136.

Preparation 154b: Methyl3-({[(4R)-7-[(4-ethylphenyl)(methyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 48% yield from Preparation 126b and4-ethyl-N-methylaniline according to the general procedure outlined forPreparation 126c. [M+H] Calc'd for C₂₆H₂₉N₃O₃, 432; Found, 432.

Example 154:3-({[(4R)-7-[(4-ethylphenyl)(methyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 82% yield from Preparation 154baccording to the procedure for Example 1. ¹H NMR (300 MHz, DMSO-d₆): δ1.15 (3H, t, J=7.5 Hz), 1.80-1.85 (1H, m), 1.90-1.97 (1H, m), 2.54 (2H,q, J=7.5 Hz), 3.00-3.04 (1H, m), 3.15 (3H, s), 3.40-3.47 (1H, m), 3.62(1H, dd, J=5.1, 13.5 Hz), 4.06-4.14 (2H, m), 6.23 (1H, d, J=2.1 Hz),6.38 (1H, dd, J=8.1, 2.4 Hz), 6.95 (2H, d, J=8.1 Hz), 7.12 (3H, dd,J=3.6, 8.1 Hz), 7.55 (1H, d, J=4.8 Hz), 7.82 (1H, d, J=4.8 Hz), 8.37(1H, s). [M+H] Calc'd for C₂₅H₂₇N₃O₃, 418; Found, 418.

Preparation 155a: Tert-ButylN-{[(1R)-6-[methyl(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}carbamate

To a suspension of Preparation 139a (200 mg, 0.69 mmol),4-bromo-1-methyl-1,2-dihydropyridin-2-one (259 mg, 1.38 mmol), S-phos(45 mg, 0.11 mmol) and Cs₂CO₃ (315 mg, 0.97 mmol) in toluene (20 mL) wasadded Pd₂dba₃ (64 mg, 0.07 mmol) at r.t. under N₂. The reaction wasstirred at 120° C. overnight. The reaction was cooled, filtered, andconcentrated. The residue was purified by silica gel chromatography(DCM:MeOH=15:1) to give 162 mg (59%) of the title compound as a yellowoil. [M+H] Calc'd for C₂₃H₃₁N₃O₃, 398; Found, 398.

Preparation 155b:4-{[(5R)-5-(aminomethyl)-5,6,7,8-tetrahydronaphthalen-2-yl](methyl)amino}-1-methyl-1,2-dihydropyridin-2-one

The title compound was prepared in 54% yield from Preparation 155aaccording to the procedure for Preparation 43b. [M+H] Calc'd forC₁₈H₂₃N₃O, 298; Found, 298.

Preparation 155c: Methyl3-({[(1R)-6-[methyl(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 65% yield from Preparation 155baccording to the procedure for Preparation 4d. [M+H] Calc'd forC₂₅H₂₈N₄O₃, 433; Found, 433.

Example 155:3-({[(1R)-6-[methyl(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 42% yield from Preparation 155caccording to the procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ1.76-1.87 (4H, m), 2.67-2.78 (2H, m), 3.28 (3H, s), 3.41 (3H, s),3.42-3.51 (2H, m), 3.60-3.65 (1H, m), 5.45 (1H, s), 5.65-5.67 (1H, m),6.67 (2H, m), 7.31-7.38 (2H, m), 7.55 (1H, m), 7.82 (1H, s), 8.34 (1H,s). [M+H] Calc'd for C₂₄H₂₆N₄O₃, 418; Found, 419.

Preparation 156a: Tert-ButylN-{[(1R)-6-[methyl(5-methylpyrimidin-2-yl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}carbamate

The title compound was prepared in 21% yield form Preparation 139a and2-chloro-5-methylpyrimidine according to the general procedure outlinedfor Preparation 155a. [M+H] Calc'd for C₂₂H₃₀N₄O₂, 383; Found, 383.

Preparation 156b:N-[(5R)-5-(aminomethyl)-5,6,7,8-tetrahydronaphthalen-2-yl]-N,5-dimethylpyrimidin-2-amine

The title compound was prepared in 98% yield from Preparation 156aaccording to the procedure for Preparation 43b. [M+H] Calc'd forC₁₇H₂₂N₄, 283; Found, 283.

Preparation 156c: Methyl3-({[(1R)-6-[methyl(5-methylpyrimidin-2-yl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 59% yield from Preparation 156baccording to the procedure for Preparation 4d. [M+H] Calc'd forC₂₄H₂₇N₅O₂, 418; Found, 418.

Example 156:3-({[(1R)-6-[methyl(5-methylpyrimidin-2-yl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 57% yield from Preparation 156caccording to the procedure for Example 1. ¹H NMR (300 MHz, DMSO-d₆): δ1.68-1.71 (1H, m), 1.83-1.86 (3H, m), 2.09 (3H, s), 2.67-2.73 (2H, m),3.09-3.12 (1H, m), 3.39 (3H, s), 3.42-3.48 (1H, m), 3.62 (1H, dd, J=4.8,12.8 Hz), 7.02 (1H, s), 7.06 (1H, d, J=8.4 Hz), 7.32 (1H, d, J=8.4 Hz),7.58 (1H, d, J=4.8 Hz), 7.84 (1H, d, J=4.8 Hz), 8.21 (2H, s), 8.38 (1H,s). [M+H] Calc'd for C₂₃H₂₅N₅O₂, 403; Found, 404.

Preparation 157a: 5-ethyl-N-methylpyridin-2-amine

A solution of 5-ethylpyridin-2-amine (330 mg, 2.70 mmol) in THF (10 mL)was cooled to −78° C. and n-BuLi (1.2 mL, 3.0 mmol) was added. Thereaction stirred at −78° C. for 30 min, and then MeI (423 mg, 2.97 mmol)was added. The reaction was stirred for 2 h while warming to r.t. Water(10 mL) was added, and the solution was extracted with EtOAc (20 mL).The organic layer was dried (Na₂SO₄) and concentrated. The residue waspurified by silica gel chromatography (PE:EtOAc=5:1) to give 35 mg (9%)of the title compound as a yellow oil. [M+H] Calc'd for C₈H₁₂N₂, 137;Found, 137.

Preparation 157b: Methyl3-({[(4R)-7-[(5-ethylpyridin-2-yl)(methyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 42% yield from Preparation 126b and5-ethyl-N-methylpyridin-2-amine according to the general procedureoutlined for Preparation 126c. [M+H] Calc'd for C₂₅H₂₈N₄O₃, 433; Found,433.

Example 157:3-({[(4R)-7-[(5-ethylpyridin-2-yl)(methyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 80% yield from Preparation 157baccording to the procedure for Example 1. ¹H NMR (300 MHz, DMSO-d₆): δ1.13 (3H, t, J=7.5 Hz), 1.88-2.03 (2H, m), 2.44-2.50 (2H, m), 3.11-3.13(1H, m), 3.49 (3H, s), 3.47-3.50 (1H, m), 3.67-3.74 (1H, m), 4.17-4.23(2H, m), 6.56 (1H, d, J=8.7 Hz), 6.64 (1H, m), 6.72-6.76 (1H, m), 7.33(2H, d, J=8.1 Hz), 7.58 (1H, d, J=5.1 Hz), 7.83 (1H, d, J=4.8 Hz), 8.01(1H, d, J=1.8 Hz), 8.37 (1H, s). [M+H] Calc'd for C₂₄H₂₆N₄O₃, 419;Found, 419.

Preparation 158a: [4-(methylamino)phenyl]methanol

To a solution of methyl 4-(methylamino)benzoate (2.0 g, 12.1 mmol) inTHF (30 mL) was added LAH (6.1 mL, 2.4 M in THF, 14.5 mmol) at 0° C. Thereaction was stirred at r.t. for 2 h. The reaction was quenched withEtOAc (50 mL) and water (2 mL). The mixture was dried (Na₂SO₄) andconcentrated. Purification by silica gel chromatography (PE:EtOAc=3:1)gave 1.0 g (60%) of the title compound as a yellow oil. [M+H] Calc'd forC₈H₁₁NO, 138; Found 138.

Preparation 158b:4-{[(tert-butyldimethylsilyl)oxy]methyl}-N-methylaniline

To a solution of [4-(methylamino)phenyl]methanol (500 mg, 3.7 mmol) andimidazole (248 mg, 3.7 mmol) in DCM (20 mL) was added TBSCl (548 mg, 3.7mmol) at r.t., and the reaction was stirred for 2 h. The reaction wasdiluted with water (50 mL) and extracted with DCM (50 mL×3). Organicswere washed with brine (50 mL), dried (Na₂SO₄), and concentrated. Theresidue was purified by silica gel chromatography (PE:EtOAc=40:1) togive 600 mg (66%) of the title compound as a yellow oil. [M+H] Calc'dfor C₁₄H₁₅NOSi, 252; Found 252.

Preparation 158c: Methyl3-{[(1R)-6-[(4-{[(tert-butyldimethylsilyl)oxy]methyl}phenyl)-(methyl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 28% yield from Preparation 126b andPreparation 158b according to the general procedure outlined forPreparation 126c. [M+H] Calc'd for C₃₂H₄₃N₃O₃Si, 546; Found, 546.

Example 158:3-({[(1R)-6-{[4-(hydroxymethyl)phenyl](methyl)amino}-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylicAcid

To a solution of Preparation 158c (80 mg, 0.15 mmol) in THF (5 mL) wasadded TBAF (0.29 mL, 1.0 M in THF, 0.29 mmol) at r.t., and the reactionwas stirred for 1 h. Water (5 mL) and LiOH.H₂O (26 mg, 0.60 mmol) wereadded, and the reaction was stirred at r.t. for 2 h. THF was removed invacuo, and the residue was acidified to pH=5 with 1.0 N aqueous HClsolution. The precipitate was filtered and purified by prep-HPLC to give40 mg (65%) of the title compound as a yellow solid. ¹H NMR (400 MHz,DMSO-d₆): δ 1.65-1.68 (1H, m), 1.77-1.84 (3H, m), 2.64-2.67 (2H, m),3.03-3.06 (1H, m), 3.20 (3H, s), 3.41-3.46 (1H, m), 3.55-3.60 (1H, m),4.41 (2H, s), 5.01 (1H, br s), 6.72-6.76 (2H, m), 6.92 (2H, d, J=8.4Hz), 7.19-7.21 (3H, m), 7.56 (1H, d, J=4.8 Hz), 7.83 (1H, d, J=5.2 Hz),8.35 (1H, s). [M+H] Calc'd for C₂₅H₂₇N₃O₃, 418; Found, 418.

Preparation 159a: Methyl3-({[(1R)-6-[methyl(1-methyl-1H-pyrazol-4-yl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

To a suspension of Preparation 122a (300 mg, 0.796 mmol),N,1-dimethyl-1H-pyrazol-4-amine (106 mg, 0.955 mmol), S-phos (49 mg,0.119 mmol) and Cs₂CO₃ (363 mg, 1.114 mmol) in toluene (30 mL) was addedPd₂dba₃ (73 mg, 0.080 mmol) at r.t. under N₂. The reaction was stirredat 120° C. overnight. The reaction was cooled, filtered, andconcentrated. The residue was purified by silica gel chromatography(PE:EtOAc=5:1) to give 100 mg (32%) of the title compound as a yellowoil. [M+H] Calc'd for C₂₃H₂₇N₅O₂, 406; Found, 406.

Example 159:3-({[(1R)-6-[methyl(1-methyl-1H-pyrazol-4-yl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 52% yield from Preparation 159aaccording to the procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ1.73-1.76 (4H, m), 2.62 (2H, m), 2.91 (1H, s), 3.09 (3H, s), 3.44-3.50(2H, m), 3.64-3.69 (1H, m), 3.78 (3H, s), 6.51-6.52 (1H, m), 6.60 (1H,m), 7.07-7.10 (1H, m), 7.29 (1H, s), 7.53-7.54 (1H, d, J=4.8 Hz), 7.60(1H, s), 7.78-7.80 (1H, m), 8.29 (1H, s). [M+H] Calc'd for C₂₂H₂₅N₅O₂,392; Found, 392.

Preparation 160a: 1-N,1-N,4-N-trimethylbenzene-1,4-diamine

The title compound was prepared in 52% overall yield from1-N,1-N-dimethylbenzene-1,4-diamine according to the general procedureoutlined for Preparation 127a. [M+H] Calc'd for C₉H₁₄N₂, 151; Found,151.

Preparation 160b: Methyl3-({[(1R)-6-{[4-(dimethylamino)phenyl](methyl)amino}-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 23% yield from Preparation 122a andPreparation 160a according to the general procedure outlined forPreparation 126c. [M+H] Calc'd for C₂₇H₃₂N₄O₂, 445; Found, 445.

Example 160:3-({[(1R)-6-{[4-(dimethylamino)phenyl](methyl)amino}-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 11% yield from Preparation 164baccording to the procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ1.61-1.64 (1H, m), 1.75-1.80 (3H, m), 2.60-2.61 (2H, m), 2.88 (6H, s),2.97-2.98 (1H, m), 3.12 (3H, s), 3.48-3.52 (2H, m), 6.42-6.49 (2H, m),6.73 (2H, d, J=6.8 Hz), 6.97 (2H, d, J=6.8 Hz), 7.07 (1H, d, J=8.0 Hz),7.55 (1H, d, J=4.8 Hz), 7.81 (1H, d, J=4.8 Hz), 8.30 (1H, s). [M+H]Calc'd for C₂₆H₃₀N₄O₂, 431; Found, 431.

Preparation 161a: Methyl3-({[(1R)-6-[(4-cyclopropylphenyl)(methyl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 28% yield from Preparation 122a and4-cyclopropyl-N-methylaniline according to the general procedureoutlined for Preparation 126c. [M+H] Calc'd for C₂₈H₃₁N₃O₂, 442; Found,442.

Example 161:3-({[(1R)-6-[(4-cyclopropylphenyl)(methyl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 93% yield from Preparation 161aaccording to the procedure for Example 1. ¹H NMR (300 MHz, DMSO-d₆): δ0.56-0.60 (2H, m), 0.84-0.90 (2H, m), 1.60-1.63 (1H, m), 1.75-1.86 (4H,m), 2.62-2.64 (2H, m), 2.97-3.01 (1H, m), 3.15 (3H, s), 3.34-3.41 (1H,m), 3.50-3.56 (1H, m), 6.65-6.69 (2H, m), 6.86 (2H, d, J=8.1 Hz), 6.97(2H, d, J=8.7 Hz), 7.15 (1H, d, J=8.4 Hz), 7.54 (1H, d, J=4.8 Hz), 7.80(1H, d, J=4.8 Hz), 8.31 (1H, s). [M+H] Calc'd for C₂₇H₂₉N₃O₂, 428;Found, 428.

Preparation 162a: Tert-ButylN-{[(1R)-6-(2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}carbamate

The title compound was prepared in 69% yield from Preparation 6d and2,3,4,5-tetrahydro-1H-1-benzazepine according to the general procedureoutlined for Preparation 9a. [M+H] Calc'd for C₂₆H₃₄N₂O₂, 407; Found,407.

Preparation 162b:[(1R)-6-(2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)-1,2,3,4-tetrahydronaphthalen-1-yl]methanamine

The title compound was prepared in quantitative yield from Preparation162a according to the procedure for Preparation 43b. [M+H] Calc'd forC₂₁H₂₆N₂, 307; Found, 307.

Preparation 162c: Methyl3-({[(1R)-6-(2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 76% yield from Preparation 162baccording to the procedure for Preparation 4d. [M+H] Calc'd forC₂₈H₃₁N₃O₂, 442; Found, 442.

Example 162:3-({[(1R)-6-(2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 65% yield from Preparation 145caccording to the procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ1.56-1.89 (8H, m), 2.58 (4H, br s), 2.93-2.99 (1H, m), 3.32-3.39 (1H,m), 3.47-3.60 (3H, m), 6.28 (1H, s), 6.33-6.37 (1H, m), 7.04-7.11 (2H,m), 7.14-7.26 (2H, m), 7.30-7.36 (1H, m), 7.56 (d, 1H, J=5.0 Hz), 7.82(1H, d, J=5.0 Hz), 8.36 (1H, s). [M+H] Calc'd for C₂₇H₂₉N₃O₂, 428;Found, 428.

Preparation 163a: 4-cyclopropyl-N-(2-methoxyethyl)aniline

Methoxyacetyl chloride (0.55 mL, 6.0 mmol) was added to a solution of4-cyclopropylaniline (800 mg, 6.0 mmol) and DIEA (1.05 mL, 6.0 mmol) inDCM, and the reaction was stirred at r.t. for 2 h. The reaction waswashed with brine, dried (MgSO₄), and concentrated to give crudeN-(4-cyclopropylphenyl)-2-methoxyacetamide.

To a solution of this N-(4-cyclopropylphenyl)-2-methoxyacetamide in THF(20 mL) was added LAH (5.0 mL, 2.4 M in THF, 12 mmol) at 0° C. Thereaction was stirred at r.t. for 2 h. The solution was diluted withwater (0.5 mL) and EtOAc (30 mL), dried (Na₂SO₄), and concentrated.Purification by silica gel chromatography (0% to 15% MeOH/DCM) gave 912mg (79%) of the title compound as a yellow oil. [M+H] Calc'd forC₁₂H₁₇NO, 192; Found, 192.

Preparation 163b: Tert-ButylN-{[(1R)-6-[(4-cyclopropylphenyl)(2-methoxyethyl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}carbamate

The title compound was prepared in 69% yield from Preparation 6d and4-cyclopropyl-N-(2-methoxyethyl)aniline according to the generalprocedure outlined for Preparation 9a. [M+H] Calc'd for C₂₈H₃₈N₂O₃, 451;Found, 451.

Preparation 163c:(5R)-5-(aminomethyl)-N-(4-cyclopropylphenyl)-N-(2-methoxyethyl)-5,6,7,8-tetrahydronaphthalen-2-amine

The title compound was prepared in quantitative yield from Preparation163b according to the procedure for Preparation 43b. [M+H] Calc'd forC₂₃H₃₀N₂O, 351; Found, 351.

Preparation 163d: Methyl3-({[(1R)-6-[(4-cyclopropylphenyl)(2-methoxyethyl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 72% yield from Preparation 163caccording to the procedure for Preparation 4d. [M+H] Calc'd forC₃₀H₃₅N₃O₃, 486; Found, 486.

Example 163:3-({[(1R)-6-[(4-cyclopropylphenyl)(2-methoxyethyl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 65% yield from Preparation 163daccording to the procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ0.58-0.62 (2H, m), 0.85-0.91 (2H, m), 1.61-1.67 (1H, m), 1.71-1.85 (4H,m), 2.60-2.65 (2H, m), 2.99-3.03 (1H, m), 3.23 (3H, s), 3.37-3.57 (4H,m), 3.75-3.80 (2H, m), 6.65 (1H, s), 6.68 (1H, d, J=8.6 Hz), 6.89 (2H,d, J=7.0 Hz), 6.97 (2H, d, J=7.8 Hz), 7.16 (1H, d, J=8.2 Hz), 7.55 (1H,d, J=4.5 Hz), 7.81 (1H, d, J=4.5 Hz), 8.32 (1H, s). [M+H] Calc'd forC₂₉H₃₃N₃O₃, 472; Found, 472.

Preparation 164a: 4-(methoxymethyl)-N-methylaniline

The title compound was prepared in 22% overall yield from4-methoxymethylaniline according to the general procedure outlined forPreparation 127a. [M+H] Calc'd for C₉H₁₃NO, 152; Found, 152.

Preparation 164b: Methyl3-({[(1R)-6-{[4-(methoxymethyl)phenyl](methyl)amino}-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 23% yield from Preparation 122a and4-(methoxymethyl)-N-methylaniline according to the general procedureoutlined for Preparation 126c. [M+H] Calc'd for C₂₇H₃₁N₃O₃, 446; Found,446.

Example 164:3-({[(1R)-6-{[4-(methoxymethyl)phenyl](methyl)amino}-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 33% yield from Preparation 164baccording to the procedure for Example 1. ¹H NMR (300 MHz, DMSO-d₆): δ1.59-1.79 (4H, m), 2.61-2.67 (2H, m), 3.02-3.04 (1H, m), 3.20 (3H, s),3.23 (3H, s), 3.31-3.40 (1H, m), 3.51-3.54 (1H, m), 4.28 (2H, s),6.77-6.88 (4H, m), 7.14-7.24 (3H, m), 7.54 (1H, d, J=4.2 Hz), 7.80 (1H,d, J=4.8 Hz), 8.31 (1H, s). [M+H] Calc'd for C₂₆H₂₉N₃O₃, 432; Found,432.

Preparation 165a: 4-((tert-butyldimethylsilyl)oxy)-N-methylaniline

A solution of 4-(methylamino)phenol (5.0 g, 29 mmol), TBDMSCl (4.8 g, 32mmol) and imidazole (9.9 g, 0.15 mol) in DCM was stirred at r.t. for 1h. Water was added, and the mixture was extracted with EtOAc. Theorganic layer was dried (Na₂SO₄), concentrated and purified by silicagel chromatography (PE:EtOAc=10:1) to give 3.0 g (43%) of the titlecompound as a dark green oil. [M+H] Calc'd for C₁₃H₂₃NOSi, 238; Found,238.

Preparation 165b: Methyl3-({[(1R)-6-({4-[(tert-butyldimethylsilyl)oxy]phenyl}-(methyl)amino)-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 36% yield from Preparation 122a and4-((tert-butyldimethylsilyl)oxy)-N-methylaniline according to thegeneral procedure outlined for Preparation 126c. [M+H] Calc'd forC₃₁H₄₁N₃O₃Si, 532; Found, 532.

Preparation 165c: Methyl3-({[(1R)-6-[(4-hydroxyphenyl)(methyl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

To a solution of Preparation 165b (733 mg, 1.37 mmol) in THF (10 mL) wasadded TBAF (3 mL, 3 mmol, 1 M) slowly. The mixture was stirred at r.t.for 20 min. EtOAc (10 mL) and then water (10 mL) was added to thesolution. The organic layer was separated, dried over Na₂SO₄,concentrated, and purified by silica gel chromatography (PE:EtOAc=2:1)to give 576 mg (100%) of the title compound as a yellow oil. [M+H]Calc'd for C₂₅H₂₇N₃O₃, 418; Found, 418.

Example 165:3-({[(1R)-6-[(4-hydroxyphenyl)(methyl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 88% yield from Preparation 165caccording to the procedure for Example 1. ¹H NMR (300 MHz, DMSO-d₆): δ1.59-1.81 (4H, m), 2.48-2.58 (2H, m), 2.92-3.00 (1H, m), 3.10 (3H, s),3.27-3.51 (2H, m), 6.41 (1H, s), 6.46 (1H, dd, J=8.7, 1.5 Hz), 7.33 (2H,d, J=8.7 Hz), 6.91 (2H, d, J=8.7 Hz), 7.06 (1H, d, J=8.1 Hz), 7.53 (1H,d, J=4.8 Hz), 7.78 (1H, d, J=4.8 Hz), 8.27 (1H, s), 9.26 (1H, br s).[M+H] Calc'd for C₂₄H₂₅N₃O₃, 404; Found, 404.

Preparation 166a: N,3,5-trimethyl-1,2-oxazol-4-amine

The title compound was prepared in 33% overall yield fromdimethyl-1,2-oxazol-4-amine according to the general procedure outlinedfor Preparation 127a. [M+H] Calc'd for C₆H₁₀N₂O, 127; Found, 127.

Preparation 166b: Methyl3-({[(1R)-6-[(dimethyl-1,2-oxazol-4-yl)(methyl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 36% yield from Preparation 122a andN,3,5-trimethyl-1,2-oxazol-4-amine according to the general procedureoutlined for Preparation 126c. [M+H] Calc'd for C₂₄H₂₈N₄O₃, 421; Found,421.

Example 166:3-({[(1R)-6-[(dimethyl-1,2-oxazol-4-yl)(methyl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 91% yield from Preparation 166baccording to the procedure for Example 1. ¹H NMR (300 MHz, DMSO-d₆): δ1.61-1.64 (1H, m), 1.73-1.82 (3H, m), 1.95 (3H, s), 2.19 (3H, s),2.62-2.66 (2H, m), 2.96-3.00 (1H, m), 3.09 (3H, s), 3.38-3.41 (1H, m),3.47-3.53 (1H, m), 6.31-6.33 (2H, m), 7.10 (1H, d, J=8.4 Hz), 7.53 (1H,d, J=5.1 Hz), 7.80 (1H, d, J=5.1 Hz), 8.31 (1H, s). [M+H] Calc'd forC₂₃H₂₆N₄O₃, 407; Found, 407.

Preparation 167a: N-methyl-4-(pyrrolidin-1-yl)aniline

The title compound was prepared in 74% overall yield from4-(pyrrolidin-1-yl)aniline according to the general procedure outlinedfor Preparation 127a. [M+H] Calc'd for C₁₁H₁₆N₂, 177; Found, 177.

Preparation 167b: Methyl3-({[(1R)-6-{methyl[4-(pyrrolidin-1-yl)phenyl]amino}-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 55% yield from Preparation 122a andN-methyl-4-(pyrrolidin-1-yl)aniline according to the general procedureoutlined for Preparation 126c. [M+H] Calc'd for C₂₉H₃₄N₄O₂, 471; Found,471.

Example 167:3-({[(1R)-6-{methyl[4-(pyrrolidin-1-yl)phenyl]amino}-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 77% yield from Preparation 167baccording to the procedure for Example 1. ¹H NMR (300 MHz, DMSO-d₆): δ1.58-1.62 (1H, m) 1.69-1.78 (3H, m), 1.89-1.94 (4H, m), 2.55-2.58 (2H,m), 2.92-2.96 (1H, m), 3.09 (3H, s), 3.30-3.33 (4H, m), 3.37-3.43 (1H,m), 3.46-3.49 (1H, m), 6.36 (1H, s), 6.42 (1H, d, J=9.0 Hz), 6.52 (2H,d, J=8.7 Hz), 6.94 (2H, d, J=8.4 Hz), 7.03 (1H, d, J=9.0 Hz), 7.53 (1H,d, J=4.8 Hz), 7.79 (1H, d, J=4.5 Hz), 8.29 (1H, s). [M+H] Calc'd forC₂₈H₃₂N₄O₂, 457; Found, 457.

Preparation 168a: [1-(4-bromophenyl)ethoxy](tert-butyl)dimethylsilane

To a solution of 1-(4-bromophenyl)ethan-1-ol (2.8 g, 13.93 mmol) andimidazole (2.84 g, 41.79 mmol) in DMF (35 mL) was added TBDMSCl (4.18 g,27.86 mmol) at r.t., and the reaction was stirred overnight. Thereaction was diluted with water (70 mL) and extracted with EtOAc (50mL×3). Organics were washed with brine (50 mL), dried (Na₂SO₄), andconcentrated. The residue was purified by silica gel chromatography(PE:EtOAc=100:1) to give 4.08 g (95%) of the title compound as acolorless oil.

Preparation 168b:4-{1-[(tert-butyldimethylsilyl)oxy]ethyl}-N-methylaniline

To a suspension of Preparation 168a (1.0 g, 3.18 mmol), KOAc (780 mg,7.96 mmol), and methylamine (16 mL, 2 M in THF) in DMF (30 mL) was addedCuI (728 mg, 3.83 mmol) at r.t. under N₂. The reaction vessel was sealedand stirred at 100° C. overnight. After filtration, the solution wasdiluted with ammonium hydroxide (10 mL) and extracted with EtOAc. Theorganic layer was concentrated in vacuo, and the residue was purified bysilica gel chromatography (PE:EtOAc=5:1) to give 490 mg (58%) of thetitle compound as a colorless oil. [M+H] Calc'd for C₁₅H₂₇NOSi, 266;Found, 266.

Preparation 168c: Methyl3-[({6-[(4-{1-[(tert-butyldimethylsilyl)oxy]ethyl}phenyl)-(methyl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl}methyl)amino]pyridine-4-carboxylate

The title compound was prepared in 32% yield from Preparation 122a andPreparation 168b according to the general procedure outlined forPreparation 126c. [M+H] Calc'd for C₃₃H₄₅N₃O₃Si, 560; Found, 560.

Preparation 168d: Methyl3-({[6-({4-[(1R)-1-hydroxyethyl]phenyl}(methyl)amino)-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate;and Preparation 169d: Methyl3-({[6-({4-[(1S)-1-hydroxyethyl]phenyl}(methyl)amino)-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

To a solution of Preparation 168c (333 mg, 0.60 mmol) in THF (5 mL) wasadded TBAF (1.2 mL, 1.0 M in THF, 1.2 mmol) at r.t., and the reactionwas stirred for 1 h. The solution was diluted with EtOAc (30 mL) andwater (10 mL), and acidified to pH=5 with 5N HCl. This mixture wasextracted with EtOAc (50 mL×3), washed with brine (50 mL), dried(Na₂SO₄), and concentrated. The residue was purified by silica gelchromatography (PE:EtOAc=1:1) to give 142 mg (54%) of the racemate as ayellow solid. [M+H] Calc'd for C₂₇H₃₁N₃O₃, 446; Found, 446.

Separation by chiral prep-HPLC (Column: Chiralcel IA 5 um 4.6*250 mm,Mobile phase: Hex:EtOH=80:20; F: 1.0 mL/min; W: 230 nm; T: 30° C.) gave50 mg (30%) of Preparation 168d (8.622 min) and 55 mg (33%) ofPreparation 169d (9.751 min), each as a yellow solid. Assignment of thehydroxyethyl stereocenter is arbitrary.

Example 168:3-({[6-({4-[(1R)-1-hydroxyethyl]phenyl}(methyl)amino)-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 15% yield from Preparation 168daccording to the procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆):δ1.30 (3H, d, J=6.4 Hz), 1.63-1.67 (1H, m), 1.77-1.84 (3H, m), 2.64-2.67(2H, m), 3.03-3.05 (1H, m), 3.20 (3H, s), 3.39-3.41 (1H, m), 3.42-3.44(1H, m), 3.54-3.58 (1H, m), 4.64-4.66 (1H, m), 5.01 (1H, s), 6.71-6.75(2H, m), 6.92 (2H, d, J=8.0 Hz), 7.19-7.24 (3H, m), 7.56 (1H, d, J=5.2Hz), 7.82 (1H, d, J=4.8 Hz), 8.33 (1H, s). [M+H] Calc'd for C₂₆H₂₉N₃O₃,432; Found, 432.

Example 169:3-({[6-({4-[(1S)-1-hydroxyethyl]phenyl}(methyl)amino)-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 17% yield from Preparation 169daccording to the procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆):δ1.30 (3H, d, J=6.4 Hz), 1.63-1.67 (1H, m), 1.75-1.82 (3H, m), 2.64-2.67(2H, m), 2.99-3.04 (1H, m), 3.20 (3H, s), 3.34-3.38 (2H, m), 3.50-3.55(1H, m), 4.63-4.67 (1H, m), 5.01 (1H, s), 6.71-6.75 (2H, m), 6.92 (2H,d, J=8.4 Hz), 7.20-7.23 (3H, m), 7.57 (1H, d, J=5.2 Hz), 7.78 (1H, d,J=4.8 Hz), 8.24 (1H, s). [M+H] Calc'd for C₂₆H₂₉N₃O₃, 432; Found, 432.

Preparation 170a: N-methyl-4-(morpholin-4-yl)aniline

The title compound was prepared in 48% overall yield from4-(morpholin-4-yl)aniline according to the general procedure outlinedfor Preparation 127a. [M+H] Calc'd for C₁₁H₁₆N₂O, 193; Found, 193.

Preparation 170b: Methyl3-({[(1R)-6-{methyl[4-(morpholin-4-yl)phenyl]amino}-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 46% yield from Preparation 122a andN-methyl-4-(morpholin-4-yl)aniline according to the general procedureoutlined for Preparation 126c. [M+H] Calc'd for C₂₉H₃₄N₄O₃, 487; Found,487.

Example 170:3-({[(1R)-6-{methyl[4-(morpholin-4-yl)phenyl]amino}-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 66% yield from Preparation 166baccording to the procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ1.62-1.63 (1H, m), 1.79-1.80 (3H, m), 2.60-2.63 (2H, m) 2.97-2.99 (1H,m), 3.05-3.07 (4H, m), 3.14 (3H, s), 3.31-3.36 (1H, m), 3.48-3.52 (1H,m), 3.72-3.74 (4H, m), 6.51 (1H, m), 6.55-6.57 (1H, m), 6.91-6.99 (4H,m), 7.11 (1H, d, J=8.4 Hz), 7.56 (1H, d, J=4.8 Hz), 7.79 (1H, d, J=4.8Hz), 8.26 (1H, s). [M+H] Calc'd for C₂₈H₃₂N₄O₃, 473; Found, 473.

Preparation 171a: Tert-ButylN-{[(1R)-6-[methyl(5-methyl-1,2-oxazol-3-yl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}carbamate

The title compound was prepared in 55% yield from Preparation 6d andN,5-dimethyl-1,2-oxazol-3-amine according to the general procedureoutlined for Preparation 9a. [M+H] Calc'd for C₂₁H₂₉N₃O₃, 372; Found,372.

Preparation 171b:N-[(5R)-5-(aminomethyl)-5,6,7,8-tetrahydronaphthalen-2-yl]-N,5-dimethyl-1,2-oxazol-3-amine

The title compound was prepared in quantitative yield from Preparation171a according to the procedure for Preparation 43b. [M+H] Calc'd forC₁₆H₂₁N₃O, 272; Found, 272.

Preparation 171c: methyl3-({[(1R)-6-[methyl(5-methyl-1,2-oxazol-3-yl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 69% yield from Preparation 171baccording to the procedure for Preparation 4d. [M+H] Calc'd forC₂₃H₂₆N₄O₃, 407; Found, 407.

Example 171:3-({[(1R)-6-[methyl(5-methyl-1,2-oxazol-3-yl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 72% yield from Preparation 171caccording to the procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ1.67-1.86 (4H, m), 2.26 (3H, s), 2.63-2.71 (2H, m), 3.02-3.11 (1H, m),3.24 (3H, s), 3.33-3.65 (2H, m), 5.80 (1H, s), 6.98-7.04 (2H, m), 7.31(1H, d, J=6.1 Hz), 7.66 (1H, d, J=4.4 Hz), 7.87 (1H, d, J=4.4 Hz), 8.39(1H, s). [M+H] Calc'd for C₂₂H₂₄N₄O₃, 393; Found, 393.

Preparation 172a: Tert-ButylN-{[(1R)-6-[(2-methoxyphenyl)(methyl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}carbamate

The title compound was prepared in 39% yield from Preparation 6d and2-methoxy-N-methylaniline according to the general procedure outlinedfor Preparation 9a. [M+H] Calc'd for C₂₄H₃₂N₂O₃, 397; Found, 397.

Preparation 172b:(5R)-5-(aminomethyl)-N-(2-methoxyphenyl)-N-methyl-5,6,7,8-tetrahydronaphthalen-2-amine

The title compound was prepared in quantitative yield from Preparation172a according to the procedure for Preparation 43b. [M+H] Calc'd forC₁₉H₂₄N₂O, 297; Found, 297.

Preparation 172c: Methyl3-({[(1R)-6-[(2-methoxyphenyl)(methyl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 44% yield from Preparation 172baccording to the procedure for Preparation 4d. [M+H] Calc'd forC₂₆H₂₉N₃O₃, 432; Found, 432.

Example 172:3-({[(1R)-6-[(2-methoxyphenyl)(methyl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 47% yield from Preparation 172caccording to the procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ1.55-1.65 (1H, m), 1.71-1.82 (3H, m), 2.57-2.62 (2H, m), 2.87-2.91 (1H,m), 3.10 (3H, s), 3.25-3.35 (2H, m), 3.73 (3H, s), 6.26-6.31 (2H, m),6.95-7.15 (4H, m), 7.22-7.29 (1H, m), 7.52 (1H, d, J=4.4 Hz), 7.65 (1H,d, J=4.4 Hz), 7.96 (s, 1H). [M+H] Calc'd for C₂₅H₂₇N₃O₃, 418; Found,418.

Preparation 173a: Tert-ButylN-{[(1R)-6-[methyl(pyridin-4-yl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}carbamate

The title compound was prepared in 59% yield from Preparation 6d and4-methylaminopyridine according to the general procedure outlined forPreparation 9a. [M+H] Calc'd for C₂₂H₂₉N₃O₂, 368; Found, 368.

Preparation 173b:N-[(5R)-5-(aminomethyl)-5,6,7,8-tetrahydronaphthalen-2-yl]-N-methylpyridin-4-amine

The title compound was prepared in quantitative yield from Preparation173a according to the procedure for Preparation 43b. [M+H] Calc'd forC₁₇H₂₁N₃, 268; Found, 268.

Preparation 173c: Methyl3-({[(1R)-6-[methyl(pyridin-4-yl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 42% yield from Preparation 173baccording to the procedure for Preparation 4d. [M+H] Calc'd forC₂₄H₂₆N₄O₂, 403; Found, 403.

Example 173:3-({[(1R)-6-[methyl(pyridin-4-yl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 23% yield from Preparation 173caccording to the procedure for Example 1. ¹H NMR (400 MHz, MeOD): δ1.75-1.84 (1H, m), 1.96-2.05 (3H, m), 2.78-2.95 (2H, m), 3.27-3.32 (1H,m), 3.49 (3H, s), 3.55-3.60 (2H, m), 6.84-6.87 (2H, m), 7.04 (1H, d,J=8.1 Hz), 7.08 (1H, s), 7.47 (1H, d, J=8.1 Hz), 7.78 (2H, br s),8.09-8.13 (3H, m). [M+H] Calc'd for C₂₃H₂₄N₄O₂, 389; Found, 389.

Preparation 174a: 4-(3,6-dihydro-2H-pyran-4-yl)-N-methylaniline

To a solution of4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyran(800 mg, 3.8 mmol), S-Phos (160 mg, 0.38 mmol), Pd₂(dba)₃ (72 mg, 0.08mmol), and K₃PO₄ (96 mg, 3.8 mmol) in toluene/H₂O (100 mL/20 mL) wasadded 4-bromo-N-methylaniline (712 mg, 3.84 mmol) under N₂. Afterstirring at 115° C. overnight, the reaction mixture was filtered andconcentrated. The residue was purified by silica gel chromatography(PE:EtOAc=10:1) to give 550 mg (76%) of the title compound as a yellowsolid. [M+H] Calc'd for C₁₂H₁₅NO, 190; Found, 190.

Preparation 174b Methyl3-({[(1R)-6-{[4-(3,6-dihydro-2H-pyran-4-yl)phenyl](methyl)amino}-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 15% yield from Preparation 122a and4-(3,6-dihydro-2H-pyran-4-yl)-N-methylaniline according to the generalprocedure outlined for Preparation 126c. [M+H] Calc'd for C₃₀H₃₃N₃O₃,484; Found, 484.

Example 174:3-({[(1R)-6-{[4-(3,6-dihydro-2H-pyran-4-yl)phenyl](methyl)amino}-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 32% yield from Preparation 174baccording to the procedure for Example 1. ¹H NMR (300 MHz, DMSO-d₆): δ1.62-1.63 (1H, m), 1.75-1.82 (2H, m), 2.38-2.42 (2H, m), 2.67-2.69 (2H,m), 3.05-3.08 (1H, m), 3.20 (3H, s), 3.46-3.49 (2H, m), 3.76-3.84 (4H,m), 4.17-4.18 (2H, m), 6.09 (1H, s), 6.80-6.86 (4H, t, J=9.0 Hz),7.22-7.24 (1H, d, J=8.1 Hz), 7.28-7.31 (2H, d, J=8.4 Hz), 7.73-7.75 (1H,d, J=5.7 Hz), 7.87-7.89 (1H, d, J=5.1 Hz), 8.39 (1H, s). [M+H] Calc'dfor C₂₉H₃₁N₃O₃, 470; Found, 470.

Preparation 175a: N-methyl-4-(oxan-4-yl)aniline

To a solution of compound 4-(3,6-dihydro-2H-pyran-4-yl)-N-methylaniline(200 mg, 1.05 mmol) in EtOAc (20 mL) under N₂ was added 10% Pd/C (50 mg)at r.t. The reaction was stirred overnight under 1 atm H₂. The reactionwas filtered through Celite and concentrated to give 180 mg (89%) as ayellow solid. [M+H] Calc'd for C₁₂H₁₅NO, 190; Found, 190.

Preparation 175b: Methyl3-({[(1R)-6-{methyl[4-(oxan-4-yl)phenyl]amino}-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 44% yield from Preparation 122a andN-methyl-4-(oxan-4-yl)aniline according to the general procedureoutlined for Preparation 126c. [M+H] Calc'd for C₃₀H₃₅N₃O₃, 486; Found,486.

Example 175:3-({[(1R)-6-{methyl[4-(oxan-4-yl)phenyl]amino}-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 93% yield from Preparation 175baccording to the procedure for Example 1. ¹H NMR (300 MHz, DMSO-d₆): δ1.57-1.64 (5H, m) 1.75-1.78 (3H, m), 2.62-2.65 (3H, m), 3.00-3.03 (1H,m), 3.17 (3H, s), 3.35-3.44 (3H, m), 3.51-3.53 (1H, m), 3.89-3.93 (2H,m), 6.70-6.73 (2H, m), 6.88 (2H, d, J=8.4 Hz), 7.11 (2H, d, J=8.4 Hz),7.18 (1H, d, J=8.4 Hz), 7.54 (1H, d, J=5.1 Hz), 7.1 (1H, d, J=5.1 Hz),8.33 (1H, s). [M+H] Calc'd for C₂₉H₃₃N₃O₃, 472; Found, 472.

Preparation 176a: 4-ethenyl-N-methylaniline

The title compound was prepared in 13% overall yield from4-ethenylaniline according to the general procedure outlined forPreparation 127a. [M+H] Calc'd for C₉H₁₁N, 134; Found, 134.

Preparation 176b: Methyl3-({[(4R)-7-[(4-ethenylphenyl)(methyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 38% yield from Preparation 126b and4-ethenyl-N-methylaniline according to the general procedure outlinedfor Preparation 126c. [M+H] Calc'd for C₂₆H₂₇N₃O₃, 430; Found, 430.

Example 176:3-({[(4R)-7-[(4-ethenylphenyl)(methyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 98% yield from Preparation 176baccording to the procedure for Example 1. ¹H NMR (300 MHz, DMSO-d₆): δ1.87-1.97 (2H, m), 3.05-3.08 (1H, m), 3.20 (3H, s) 3.42-3.49 (1H, m),3.63-3.69 (1H, m), 4.11-4.18 (2H, m), 5.06-5.10 (1H, m), 5.60-5.66 (1H,m), 6.42-6.43 (1H, m), 6.53-6.67 (2H, m), 6.90 (2H, d, J=8.4 Hz), 7.21(1H, d, J=8.1 Hz), 7.33 (2H, d, J=8.7 Hz), 7.55 (1H, d, J=4.8 Hz), 7.82(1H, d, J=4.8 Hz), 8.36 (1H, s). [M+H] Calc'd for C₂₅H₂₅N₃O₃, 416;Found, 416.

Preparation 177a: Methyl3-({[(1R)-6-[(4-methoxyphenyl)(methyl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 52% yield from Preparation 122a and4-methoxy-N-methylaniline according to the general procedure outlinedfor Preparation 126c. [M+H] Calc'd for C₂₆H₂₉N₃O₃, 432; Found, 432.

Example 177:3-({[(1R)-6-[(4-methoxyphenyl)(methyl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 84% yield from Preparation 177aaccording to the procedure for Example 1. ¹H NMR (300 MHz, DMSO-d₆): δ1.60-1.81 (4H, m), 2.59-2.63 (2H, m), 2.99-3.01 (1H, m), 3.13 (3H, s),3.37-3.56 (2H, m), 3.72 (3H, s), 6.49-6.54 (2H, m), 6.87-6.90 (2H, m),6.99-7.02 (2H, m), 7.09 (1H, d, J=8.4 Hz), 7.77 (1H, d, J=5.1 Hz), 7.87(1H, d, J=5.4 Hz), 8.38 (1H, s). [M+H] Calc'd for C₂₅H₂₇N₃O₃, 418;Found, 418.

Preparation 178a: Methyl3-({[(4R)-7-[(4-methoxyphenyl)(methyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 51% yield from Preparation 126b and4-methoxy-N-methylaniline according to the general procedure outlinedfor Preparation 126c. [M+H] Calc'd for C₂₅H₂₇N₃O₄, 434; Found, 434.

Example 178:3-({[(4R)-7-[(4-methoxyphenyl)(methyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 84% yield from Preparation 178aaccording to the procedure for Example 1. ¹H NMR (300 MHz, DMSO-d₆): δ1.80-1.94 (2H, m), 2.97-3.01 (1H, m), 3.11 (3H, s), 3.31-3.38 (1H, m),3.41-3.46 (1H, m), 3.73 (3H, s), 4.04-4.12 (2H, m), 6.08 (1H, s),6.22-6.25 (1H, m), 6.89-6.92 (2H, m), 7.02-7.07 (3H, m), 7.56 (1H, d,J=4.8 Hz), 7.82 (1H, d, J=5.1 Hz), 8.37 (1H, s). [M+H] Calc'd forC₂₄H₂₅N₃O₄, 420; Found, 420.

Preparation 179a: Methyl3-({[(4R)-7-{methyl[4-(pyrrolidin-1-yl)phenyl]amino}-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 35% yield from Preparation 126b andN-methyl-4-(pyrrolidin-1-yl)aniline according to the general procedureoutlined for Preparation 126c. [M+H] Calc'd for C₂₈H₃₂N₄O₃, 473; Found,473.

Example 179:3-({[(4R)-7-{methyl[4-(pyrrolidin-1-yl)phenyl]amino}-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 87% yield from Preparation 179aaccording to the procedure for Example 1. ¹H NMR (300 MHz, DMSO-d₆): δ1.79-1.80 (1H, m), 1.86-1.87 (5H, m), 2.97-2.98 (1H, m), 3.25-3.26 (3H,m), 3.38-3.39 (4H, m), 3.40-3.43 (1H, m), 3.55-3.56 (1H, m), 3.59-3.61(2H, m), 5.96-5.97 (1H, m) 6.12-6.14 (1H, m), 6.52-6.56 (2H, m),6.99-7.02 (3H, m), 7.53-7.55 (1H, d, J=4.8 Hz), 7.80-7.82 (1H, d, J=5.1Hz), 8.36 (1H, s). [M+H] Calc'd for C₂₇H₃₀N₄O₃, 459; Found, 459.

Preparation 180a: 1-(4-nitrophenyl)azetidine

1-Fluoro-4-nitrobenzene (5.0 g, 35.5 mmol) was added to a suspension ofazetidine HCl (3.98 g, 42.55 mmol) and K₂CO₃ (7.34 g, 53.19 mmol) inEtOH (100 mL) at r.t., and the reaction was stirred at 40° C. overnight.The reaction mixture was filtered and concentrated. The residue waspurified by silica gel chromatography (PE:EtOAc=10:1) to give compound700 mg (11%) of the title compound as a yellow solid. [M+H] Calc'd forC₉H₁₀N₂O₂, 180; Found, 180.

Preparation 180b: 4-(azetidin-1-yl)aniline

10% Pd/C (70 mg) was added to a solution of 1-(4-nitrophenyl)azetidine(0.7 g, 3.9 mmol) in EtOH (15 mL) at r.t. under N₂. After stirring under50 psi H₂ overnight, the reaction mixture was filtered through Celiteand concentrated to give 580 mg (99%) of the title compound as a brownoil. [M+H] Calc'd for C₉H₁₂N₂, 149; Found, 149.

Preparation 180c: 4-(azetidin-1-yl)-N-methylaniline

The title compound was prepared in 73% overall yield from4-(azetidin-1-yl)aniline according to the general procedure outlined forPreparation 127a. [M+H] Calc'd for C₁₀H₁₄N₂, 163; Found, 163.

Preparation 180d: Methyl3-({[(1R)-6-{[4-(azetidin-1-yl)phenyl](methyl)amino}-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 50% yield from Preparation 122a and4-(azetidin-1-yl)-N-methylaniline according to the general procedureoutlined for Preparation 126c. [M+H] Calc'd for C₂₈H₃₂N₄O₂, 457; Found,457.

Example 180:3-({[(1R)-6-{[4-(azetidin-1-yl)phenyl](methyl)amino}-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 73% yield from Preparation 180daccording to the procedure for Example 1. ¹H NMR (300 MHz, DMSO-d₆): δ1.59-1.64 (1H, m) 1.70-1.81 (3H, m), 2.24-2.29 (2H, m), 2.56-2.60 (2H,m), 2.95-3.06 (1H, m), 3.11 (3H, s), 3.30-3.42 (1H, m), 3.48-3.52 (1H,m), 3.3-3.79 (4H, m), 6.42-6.45 (4H, m), 6.93-6.95 (2H, m), 7.06-7.08(1H, m), 7.57 (1H, d, J=4.5 Hz), 7.83 (1H, d, J=5.1 Hz), 8.34 (1H, s).[M+H] Calc'd for C₂₇H₃₀N₄O₂, 443; Found, 443.

Preparation 181a: N-methyl-4-(trifluoromethoxy)aniline

The title compound was prepared in 68% overall yield from4-(trifluoromethoxy)aniline according to the general procedure outlinedfor Preparation 127a. [M+H] Calc'd for C₈H₈F₃NO, 192; Found, 192.

Preparation 181b: Methyl3-({[(1R)-6-{methyl[4-(trifluoromethoxy)phenyl]amino}-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 67% yield from Preparation 122a andN-methyl-4-(trifluoromethoxy)aniline according to the general procedureoutlined for Preparation 126c. [M+H] Calc'd for C₂₆H₂₆F₃N₃O₃, 486;Found, 486.

Example 181:3-({[(1R)-6-{methyl[4-(trifluoromethoxy)phenyl]amino}-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 94% yield from Preparation 181baccording to the procedure for Example 1. ¹H NMR (300 MHz, DMSO-d₆): δ1.63-1.84 (4H, m), 2.65-2.69 (2H, m), 3.18-3.20 (1H, m), 3.25 (3H, s)3.40-3.47 (1H, m), 3.55-3.61 (1H, m), 6.85-6.88 (4H, m), 7.16 (2H, d,J=8.7 Hz), 7.29 (1H, d, J=8.4 Hz), 7.55 (1H, d, J=5.1 Hz), 7.82 (1H, d,J=5.1 Hz), 8.35 (1H, s). [M+H] Calc'd for C₂₅H₂₄F₃N₃O₃, 472; Found, 472.

Preparation 182a: Methyl3-({[(4R)-7-{methyl[4-(trifluoromethoxy)phenyl]amino}-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 32% yield from Preparation 126b andN-methyl-4-(trifluoromethoxy)aniline according to the general procedureoutlined for Preparation 126c. [M+H] Calc'd for C₂₅H₂₄F₃N₃O₄, 488;Found, 488.

Example 182:3-({[(4R)-7-{methyl[4-(trifluoromethoxy)phenyl]amino}-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 89% yield from Preparation 182aaccording to the procedure for Example 1. ¹H NMR (300 MHz, DMSO-d₆): δ1.87-1.98 (2H, m), 3.05-3.10 (1H, m), 3.24 (3H, s), 3.44-3.51 (1H, m),3.64-3.70 (1H, m), 4.12-4.19 (2H, m), 6.45 (1H, d, J=2.4 Hz), 6.55-6.59(1H, m), 6.94-6.96 (2H, m), 7.18-7.26 (3H, m), 7.55 (1H, d, J=5.1 Hz),7.82 (1H, d, J=5.1 Hz), 8.38 (1H, s). [M+H] Calc'd for C₂₄H₂₂F₃N₃O₄,474; Found, 474.

Preparation 183a: Methyl3-({[(4R)-7-{[4-(azetidin-1-yl)phenyl](methyl)amino}-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 51% yield from Preparation 126b and4-(azetidin-1-yl)-N-methylaniline according to the general procedureoutlined for Preparation 126c. [M+H] Calc'd for C₂₇H₃₀N₄O₃, 459; Found,459.

Example 183:3-({[(4R)-7-{[4-(azetidin-1-yl)phenyl](methyl)amino}-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 81% yield from Preparation 183aaccording to the procedure for Example 1. ¹H NMR (300 MHz, DMSO-d₆): δ1.82-1.95 (2H, m), 2.24-2.31 (2H, m), 2.94-2.97 (1H, m), 3.07 (3H, s),3.29-3.37 (1H, m), 3.50-3.58 (1H, m), 3.74-3.79 (4H, m), 4.02-4.13 (2H,m), 5.99 (1H, d, J=2.4 Hz), 6.16 (1H, dd, J=8.7 Hz, 2.4 Hz), 6.40 (2H,d, J=8.4 Hz), 6.94 (2H, d, J=8.7 Hz), 7.03 (1H, d, J=8.4 Hz), 7.54 (1H,d, J=4.8 Hz), 7.77 (1H, d, J=4.8 Hz), 8.25 (1H, s). [M+H] Calc'd forC₂₆H₂₈N₄O₃, 445; Found, 445.

Preparation 184a: 4-(difluoromethoxy)-N-methylaniline

The title compound was prepared in 82% yield from4-(difluoromethoxy)aniline according to the general procedure outlinedfor Preparation 127a. ¹H NMR (400 MHz, CDCl₃): δ 2.82 (3H, s), 3.75 (1H,br s), 6.37 (1H, t, J=75.0 Hz), 6.56 (2H, d, J=7.1 Hz), 6.98 (2H, d,J=8.4 Hz). [M+H] Calc'd for C₈H₉F₂NO, 174; Found, 174.

Preparation 184b: tert-butylN-{[(1R)-6-{[4-(difluoromethoxy)phenyl](methyl)amino}-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}carbamate

The title compound was prepared in 59% yield from Preparation 6d andPreparation 184a according to the general procedure outlined forPreparation 9a. [M+H] Calc'd for C₂₄H₃₀F₂N₂O₃, 433; Found, 433.

Preparation 184c:(5R)-5-(aminomethyl)-N-[4-(difluoromethoxy)phenyl]-N-methyl-5,6,7,8-tetrahydronaphthalen-2-amine

The title compound was prepared in quantitative yield from Preparation184b according to the procedure for Preparation 43b. [M+H] Calc'd forC₁₉H₂₂F₂N₂O, 333; Found, 333.

Preparation 184d: Methyl3-({[(1R)-6-{[4-(difluoromethoxy)phenyl](methyl)amino}-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 76% yield from Preparation 184caccording to the procedure for Preparation 4d. [M+H] Calc'd forC₂₆H₂₇F₂N₃O₃, 468; Found, 468.

Example 184:3-({[(1R)-6-{[4-(difluoromethoxy)phenyl](methyl)amino}-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 84% yield from Preparation 184daccording to the procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ1.64-1.91 (4H, m), 2.65-2.70 (2H, m), 3.03-3.07 (1H, m), 3.32 (3H, s),3.40-3.46 (1H, m), 3.54-3.59 (1H, m), 6.76-6.80 (2H, m), 6.90-7.28 (6H,m), 7.56 (1H, d, J=4.5 Hz), 7.77 (1H, br s), 7.82 (1H, d, J=4.5 Hz),8.33 (1H, s). [M+H] Calc'd for C₂₅H₂₅F₂N₃O₃, 454; Found, 454.

Preparation 185a: 4-ethoxy-N-methylaniline

The title compound was prepared in 61% overall yield from4-ethoxyaniline according to the general procedure outlined forPreparation 127a. [M+H] Calc'd for C₉H₁₃NO, 152; Found, 152.

Preparation 185b: Methyl3-({[(1R)-6-[(4-ethoxyphenyl)(methyl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 28% yield from Preparation 122a and4-ethoxy-N-methylaniline according to the general procedure outlined forPreparation 126c. [M+H] Calc'd for C₂₇H₃₁N₃O₃, 446; Found, 446.

Example 185:3-({[(1R)-6-[(4-ethoxyphenyl)(methyl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 33% yield from Preparation 185baccording to the procedure for Example 1. ¹H NMR (300 MHz, DMSO-d₆): δ1.32 (3H, t, J=6.9 Hz), 1.62-1.78 (4H, m), 2.62-2.63 (2H, m), 2.95-2.97(1H, m), 3.15 (3H, s), 3.26-3.33 (1H, m), 3.45-3.51 (1H, m), 3.99 (2H,q, J=6.9 Hz), 6.51-6.57 (2H, m), 6.88 (2H, d, J=8.7 Hz), 7.00 (2H, d,J=8.7 Hz), 7.12 (1H, d, J=8.4 Hz), 7.57 (1H, d, J=5.1 Hz), 7.77 (1H, d,J=5.1 Hz), 8.20 (1H, s). [M+H] Calc'd for C₂₆H₂₉N₃O₃, 432; Found, 432.

Preparation 186a: Methyl3-({[(4R)-7-[(4-ethoxyphenyl)(methyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 58% yield from Preparation 126b and4-ethoxy-N-methylaniline according to the general procedure outlined forPreparation 126c. [M+H] Calc'd for C₂₆H₂₉N₃O₄, 448; Found, 448.

Example 186:3-({[(4R)-7-[(4-ethoxyphenyl)(methyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 94% yield from Preparation 186aaccording to the procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ1.32 (3H, t, J=6.8 Hz), 1.81-1.84 (1H, m), 1.92-1.98 (1H, m), 2.99-3.02(1H, m), 3.13 (3H, s), 3.39-3.45 (1H, m), 3.59-3.63 (1H, m), 4.00 (2H,q, J=6.8 Hz), 4.06-4.16 (2H, m), 6.10 (1H, d, J=2.0 Hz), 6.25 (2H, dd,J=8.8 Hz, 2.0 Hz), 6.91 (2H, d, J=8.8 Hz), 7.04 (2H, d, J=8.8 Hz), 7.07(2H, d, J=8.8 Hz), 7.03-7.09 (3H, m), 7.56 (1H, d, J=4.8 Hz), 7.83 (1H,d, J=4.8 Hz), 8.37 (1H, s). [M+H] Calc'd for C₂₅H₂₇N₃O₄, 434; Found,434.

Preparation 187a: N-methyl-4-(propan-2-yl)aniline

A mixture of 1-bromo-4-isopropylbenzene (1.0 g, 5.03 mmol), methylamine(25 mL, 50.0 mmol), CuI (1.15 g, 6.0 mmol), KOAc (1.24 g, 12.6 mmol) andDMF (30 mL) in a sealed tube under N₂ was heated to 100° C. overnight.The mixture was cooled to r.t., diluted with water (100 mL), andextracted with EtOAc. The organic layer was dried (Na₂SO₄),concentrated, and purified by silica gel chromatography (PE:EtOAc=10:1)to give 254 mg (34%) of the title compound as a yellow oil. [M+H] Calc'dfor C₁₀H₁₅N, 150; Found, 150.

Preparation 187b: Methyl3-({[(4R)-7-{methyl[4-(propan-2-yl)phenyl]amino}-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 57% yield from Preparation 126b andN-methyl-4-(propan-2-yl)aniline according to the general procedureoutlined for Preparation 126c. [M+H] Calc'd for C₂₇H₃₁N₃O₃, 446; Found,446.

Example 187:3-({[(4R)-7-{methyl[4-(propan-2-yl)phenyl]amino}-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 90% yield from Preparation 187baccording to the procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ1.19 (6H, d, J=6.8 Hz), 1.83-1.99 (2H, m), 2.81-2.88 (1H, m), 3.02-3.05(1H, m), 3.17 (3H, s), 3.44-3.48 (1H, m), 3.62-3.66 (1H, m), 4.09-4.19(2H, m), 6.25 (1H, d, J=1.6 Hz), 6.40 (1H, dd, J=8.4 Hz, 1.6 Hz), 6.97(2H, d, J=8.0 Hz), 7.13 (1H, d, J=8.4 Hz), 7.17 (2H, d, J=8.0 Hz), 7.57(1H, d, J=5.2 Hz), 7.83 (1H, d, J=5.2 Hz), 8.38 (1H, s). [M+H] Calc'dfor C₂₆H₂₉N₃O₃, 432; Found, 432.

Preparation 188a: N-methyl-4-(1H-pyrazol-1-yl)aniline

The title compound was prepared in 98% overall yield from4-(1H-pyrazol-1-yl)aniline according to the general procedure outlinedfor Preparation 127a. [M+H] Calc'd for C₁₀H₁₁N₃, 174; Found, 174.

Preparation 188b: Methyl3-({[(1R)-6-{methyl[4-(1H-pyrazol-1-yl)phenyl]amino}-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 32% yield from Preparation 122a andN-methyl-4-(1H-pyrazol-1-yl)aniline according to the general procedureoutlined for Preparation 126c. [M+H] Calc'd for C₂₈H₂₉N₅O₂, 468; Found,468.

Example 188:3-({[(1R)-6-{methyl[4-(1H-pyrazol-1-yl)phenyl]amino}-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 57% yield from Preparation 188baccording to the procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ1.64-1.69 (1H, m), 1.79-1.85 (3H, m), 2.67-2.70 (2H, m), 3.07-3.08 (1H,m), 3.26 (3H, s), 3.42-3.47 (1H, m), 3.57-3.61 (1H, m), 6.49 (1H, s),6.84 (1H, s), 6.86 (1H, d, J=8.4 Hz), 6.99 (2H, d, J=8.8 Hz), 7.27 (1H,d, J=8.4 Hz), 7.57 (1H, d, J=4.8 Hz), 7.66 (2H, d, J=8.8 Hz), 7.68 (1H,s), 7.83 (1H, d, J=4.8 Hz), 8.35 (2H, s). [M+H] Calc'd for C₂₇H₂₇N₅O₂,454; Found, 454.

Preparation 189a: Methyl3-({[(4R)-7-{methyl[4-(1H-pyrazol-1-yl)phenyl]amino}-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 52% yield from Preparation 126b andN-methyl-4-(1H-pyrazol-1-yl)aniline according to the general procedureoutlined for Preparation 126c. [M+H] Calc'd for C₂₇H₂₇N₅O₃, 470; Found,470.

Example 189:3-({[(4R)-7-{methyl[4-(1H-pyrazol-1-yl)phenyl]amino}-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 83% yield from Preparation 189aaccording to the procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ1.85-1.90 (1H, m), 1.97-2.02 (1H, m), 3.07-3.10 (1H, m), 3.24 (3H, s),3.46-3.52 (1H, m), 3.66-3.71 (1H, m), 4.11-4.22 (2H, m), 6.43 (1H, s),6.50 (1H, s), 6.55 (1H, d, J=8.4 Hz), 7.08 (2H, d, J=8.8 Hz), 7.23 (1H,d, J=8.4 Hz), 7.57 (1H, d, J=5.2 Hz), 7.69 (1H, s), 7.70 (2H, d, J=8.8Hz), 7.85 (1H, d, J=5.2 Hz), 8.38 (1H, s), 8.41 (1H, s). [M+H] Calc'dfor C₂₆H₂₅N₅O₃, 456; Found, 456.

Preparation 190a: 4-(difluoromethoxy)-N-methylaniline

The title compound was prepared in 29% overall yield from4-(difluoromethoxy)aniline according to the general procedure outlinedfor Preparation 127a. [M+H] Calc'd for C₈H₉F₂NO, 174; Found, 174.

Preparation 190b: Methyl3-({[(4R)-7-{[4-(difluoromethoxy)phenyl](methyl)amino}-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 75% yield from Preparation 126b and4-(difluoromethoxy)-N-methylaniline according to the general procedureoutlined for Preparation 126c. [M+H] Calc'd for C₂₅H₂₅F₂N₃O₄, 470;Found, 470.

Example 190:3-({[(4R)-7-{[4-(difluoromethoxy)phenyl](methyl)amino}-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 89% yield from Preparation 190baccording to the procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ1.83-1.87 (1H, m), 1.94-2.01 (1H, m), 3.04-3.08 (1H, m), 3.19 (3H, s),3.43-3.49 (1H, m), 3.63-3.68 (1H, m), 4.10-4.20 (2H, m), 6.34 (1H, s),6.47 (1H, d, J=8.0 Hz), 7.03 (2H, d, J=8.8 Hz), 7.10 (2H, d, J=8.8 Hz),7.13 (1H, t, J=74.8 Hz), 7.19 (1H, d, J=8.8 Hz), 7.57 (1H, d, J=4.8 Hz),7.83 (1H, d, J=4.8 Hz), 8.38 (1H, s). [M+H] Calc'd for C₂₄H₂₃F₂N₃O₄,456; Found, 456.

Preparation 191a: Tert-ButylN-{[(1R)-6-[methyl(phenyl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}carbamate

The title compound was prepared in 69% yield from Preparation 6d andN-methylaniline according to the general procedure for Preparation 9a.[M+H] Calc'd for C₂₃H₃₀N₂O₂, 367; Found, 367.

Preparation 191b:(5R)-5-(aminomethyl)-N-methyl-N-phenyl-5,6,7,8-tetrahydronaphthalen-2-amine

The title compound was prepared in 96% yield from Preparation 191aaccording to the procedure for Preparation 43b. [M+H] Calc'd forC₁₈H₂₂N₂, 267; Found, 267.

Preparation 191c:6-chloro-3-({[(1R)-6-[methyl(phenyl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridazine-4-carboxylicAcid

A 0.3 M solution of Preparation 191b (132 mg, 0.5 mmol) in 1-butanol wascombined with 3,6-dichloropyridazine-4-carboxylic acid (97 mg, 0.5 mmol)and DIEA (304 μL, 1.8 mmol). The reaction mixture was capped and heatedto 80° C. for 14 h. The mixture was diluted with water (10 mL) andextracted with EtOAc (3×15 mL). The combined organic layers were washedwith saturated bicarbonate solution (30 mL) and brine (30 mL), dried(Na₂SO₄), filtered, and concentrated in vacuo. The resulting orangesolid (190 mg) was carried forward without any further purification. ¹HNMR (400 MHz, DMSO-d₆) δ 1.59-1.90 (m, 4H) 2.62-2.73 (m, 2H) 3.10-3.17(m, 1H) 3.22 (s, 3H) 3.56-3.69 (m, 1H) 3.80-3.92 (m, 1H) 6.76-6.94 (m,5H) 7.19-7.27 (m, 3H) 7.75-7.79 (m, 1H) 8.15-8.28 (m, 1H). [M+H] Calc'dfor C₂₃H₂₃ClN₄O₂, 423; Found, 423.

Example 191:3-({[(1R)-6-[methyl(phenyl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridazine-4-carboxylicAcid

A solution of Preparation 191c (171 mg, 0.4 mmol) in MeOH (7.1 mL) wastreated with ammonium formate (51 mg, 0.8 mmol), and 10% Pd/C (Degussa)(25 mg). The reaction mixture was heated to 50° C. using microwaveirradiation for 2 h. The crude reaction mixture was filtered through ashort plug of Celite, washing with MeOH (˜30 mL). The resulting filtratewas concentrated in vacuo. The residue was diluted with EtOAc (25 ml),washed with water, dried (MgSO₄), filtered, and concentrated in vacuo.The resulting residue was purified by prep-HPLC to give 21 mg (14%) ofthe title compound as a tan solid. ¹H NMR (400 MHz, DMSO-d₆) δ 1.61-1.91(m, 4H) 2.61-2.74 (m, 2H) 3.06-3.18 (m, 1H) 3.22 (s, 3H) 3.53-3.68 (m,1H) 3.85-3.96 (m, 1H) 6.75-6.89 (m, 3H) 6.89-6.95 (m, 2H) 7.19-7.28 (m,3H) 7.67-7.75 (m, 1H) 8.10-8.17 (m, 1H) 8.57-8.63 (m, 1H). [M+H] Calc'dfor C₂₃H₂₄N₄O₂, 389; Found, 389.

Preparation 192a: N-methyl-4-(2,2,2-trifluoroethyl)aniline

The title compound was prepared in 77% yield from1-bromo-4-(2,2,2-trifluoroethyl)benzene according to the procedurePreparation 187a. [M+H] Calc'd for C₉H₁₀F₃N, 190; Found, 190.

Preparation 192b: Methyl3-({[(4R)-7-{methyl[4-(2,2,2-trifluoroethyl)phenyl]amino}-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 47% yield from Preparation 126b andN-methyl-4-(2,2,2-trifluoroethyl)aniline according to the generalprocedure outlined for Preparation 126c. [M+H] Calc'd for C₂₆H₂₆F₃N₃O₃,486; Found, 486.

Example 192:3-({[(4R)-7-{methyl[4-(2,2,2-trifluoroethyl)phenyl]amino}-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 88% yield from Preparation 192baccording to the procedure for Example 1. ¹H NMR (300 MHz, DMSO-d₆): δ1.84-1.88 (1H, m), 1.95-2.02 (1H, m), 3.06-3.10 (1H, m), 3.20 (3H, s),3.46-3.58 (3H, m), 3.66-3.70 (1H, m), 4.11-4.22 (2H, m), 6.42 (1H, s),6.54 (1H, d, J=8.8 Hz), 6.95 (2H, d, J=8.0 Hz), 7.20-7.23 (3H, m), 7.57(1H, d, J=4.8 Hz), 7.85 (1H, d, J=4.8 Hz), 8.40 (1H, s). [M+H] Calc'dfor C₂₅H₂₄F₃N₃O₃, 472; Found, 472.

Preparation 193a: 4-(1H-imidazol-1-yl)-N-methylaniline

The title compound was prepared in 33% overall yield from4-(1H-imidazol-1-yl)aniline according to the general procedure outlinedfor Preparation 127a. [M+H] Calc'd for C₁₀H₁₁N₃, 174; Found, 174.

Preparation 193b: Methyl3-({[(1R)-6-{[4-(1H-imidazol-1-yl)phenyl](methyl)amino}-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 43% yield from Preparation 122a and4-(1H-imidazol-1-yl)-N-methylaniline according to the general procedureoutlined for Preparation 126c. [M+H] Calc'd for C₂₈H₂₉N₅O₂, 468; Found,468.

Example 193:3-({[(1R)-6-{[4-(1H-imidazol-1-yl)phenyl](methyl)amino}-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 82% yield from Preparation 193baccording to the procedure for Example 1. ¹H NMR (300 MHz, DMSO-d₆): δ1.64-1.69 (1H, m), 1.79-1.85 (3H, m), 2.66-2.71 (2H, m), 3.07-3.08 (1H,m), 3.26 (3H, s), 3.39-3.44 (1H, m), 3.56-3.60 (1H, m), 6.86-6.90 (2H,m), 6.97-6.99 (2H, m), 7.07 (1H, s), 7.30 (1H, d, J=6.3 Hz), 7.46 (2H,d, J=6.3 Hz), 7.57-7.62 (2H, m), 7.81 (1H, d, J=3.6 Hz), 8.11 (1H, s),8.31 (1H, s). [M+H] Calc'd for C₂₇H₂₇N₅O₂, 454; Found, 454.

Preparation 194a: Methyl3-({[(4R)-7-{[4-(1H-imidazol-1-yl)phenyl](methyl)amino}-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 72% yield from Preparation 126b and4-(1H-imidazol-1-yl)-N-methylaniline according to the general procedureoutlined for Preparation 126c. [M+H] Calc'd for C₂₇H₂₇N₅O₃, 470; Found,470.

Example 194:3-({[(4R)-7-{[4-(1H-imidazol-1-yl)phenyl](methyl)amino}-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 81% yield from Preparation 194aaccording to the procedure for Example 1. ¹H NMR (300 MHz, DMSO-d₆): δ1.87-1.90 (1H, m), 1.98-2.00 (1H, m), 3.06-3.09 (1H, m), 3.25 (3H, s),3.43-3.48 (1H, m), 3.64-3.69 (1H, m), 4.13-4.20 (2H, m), 6.46 (1H, s),6.58 (1H, d, J=6.0 Hz), 7.04-7.08 (3H, m), 7.25 (1H, d, J=6.3 Hz), 7.50(2H, d, J=6.3 Hz), 7.58 (1H, d, J=3.6 Hz), 7.64 (1H, s), 7.82 (1H, d,J=3.3 Hz), 8.13 (1H, s), 8.35 (1H, s). [M+H] Calc'd for C₂₆H₂₅N₅O₃, 456;Found, 456.

Preparation 195a: 4-(3,3-difluoroazetidin-1-yl)-N-methylaniline

The title compound was prepared in 10% overall yield from3,3-difluoroazetidine hydrochloride according to the general schemeoutlined for Preparations 180a, 180b, and 180c. [M+H] Calc'd forC₁₀H₁₂F₂N₂, 199; Found, 199.

Preparation 195b: Methyl3-({[(1R)-6-{[4-(3,3-difluoroazetidin-1-yl)phenyl](methyl)amino}-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 39% yield from Preparation 122a and4-(3,3-difluoroazetidin-1-yl)-N-methylaniline according to the generalprocedure outlined for Preparation 126c. [M+H] Calc'd for C₂₇H₂₈F₂N₄O₂,479; Found, 479.

Example 195:3-({[(1R)-6-{[4-(3,3-difluoroazetidin-1-yl)phenyl](methyl)amino}-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 90% yield from Preparation 195baccording to the procedure for Example 1. ¹H NMR (300 MHz, DMSO-d₆): δ1.59-1.65 (1H, m), 1.76-1.81 (3H, m), 2.57-2.63 (2H, m), 2.96-3.01 (1H,m), 3.14 (3H, s), 3.33-3.41 (1H, m), 3.47-3.54 (1H, m), 4.24 (4H, t,J=12.3 Hz), 6.48 (1H, s), 6.51 (1H, d, J=8.8 Hz), 6.57 (2H, d, J=8.4Hz), 7.00 (2H, d, J=8.4 Hz), 7.09 (1H, d, J=8.8 Hz), 7.55 (1H, d, J=4.8Hz), 7.81 (1H, d, J=4.8 Hz), 8.32 (1H, s). [M+H] Calc'd forC₂₇H₂₈F₂N₄O₂, 479; Found, 479.

Preparation 196a: Methyl3-({[(4R)-7-{[4-(3,3-difluoroazetidin-1-yl)phenyl](methyl)amino}-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 35% yield from Preparation 126b and4-(3,3-difluoroazetidin-1-yl)-N-methylaniline according to the generalprocedure outlined for Preparation 126c. [M+H] Calc'd for C₂₇H₂₈F₂N₄O₃,495; Found, 495.

Example 196:3-({[(4R)-7-{[4-(3,3-difluoroazetidin-1-yl)phenyl](methyl)amino}-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 86% yield from Preparation 196aaccording to the procedure for Example 1. ¹H NMR (300 MHz, DMSO-d₆): δ1.78-1.86 (1H, m), 1.90-1.98 (1H, m), 2.97-3.02 (1H, m), 3.12 (3H, s),3.40-3.47 (1H, m), 3.59-3.65 (1H, m), 4.05-4.14 (2H, m), 4.25 (4H, t,J=12.0 Hz), 6.07 (1H, s), 6.23 (1H, d, J=6.6 Hz), 6.58 (2H, d, J=8.4Hz), 7.03 (2H, d, J=8.4 Hz), 7.06 (1H, d, J=6.6 Hz), 7.56 (1H, d, J=3.9Hz), 7.84 (1H, d, J=3.9 Hz), 8.37 (1H, s). [M+H] Calc'd forC₂₆H₂₆F₂N₄O₃, 481; Found, 481.

Preparation 197a: 4-(2-methoxyethoxy)-N-methylaniline

The title compound was prepared in 88% yield from4-(2-methoxyethoxy)aniline according to the general procedure outlinedfor Preparation 127a. [M+H] Calc'd for C₁₀H₁₅NO₂, 182; Found, 182.

Preparation 197b: Tert-ButylN-{[(1R)-6-{[4-(2-methoxyethoxy)phenyl](methyl)amino}-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}carbamate

The title compound was prepared in 53% yield from Preparation 6d andPreparation 197a according to the general procedure outlined forPreparation 9a. [M+H] Calc'd for C₂₆H₃₆N₂O₄, 441; Found, 441.

Preparation 197c:(5R)-5-(aminomethyl)-N-[4-(2-methoxyethoxy)phenyl]-N-methyl-5,6,7,8-tetrahydronaphthalen-2-amine

The title compound was prepared in quantitative yield from Preparation197b according to the procedure for Preparation 43b. [M+H] Calc'd forC₂₁H₂₈N₂O₂, 341; Found, 341.

Preparation 197d: Methyl3-({[(1R)-6-{[4-(2-methoxyethoxy)phenyl](methyl)amino}-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 52% yield from Preparation 197caccording to the procedure for Preparation 4d. [M+H] Calc'd forC₂₈H₃₃N₃O₄, 476; Found, 476.

Example 197:3-({[(1R)-6-{[4-(2-methoxyethoxy)phenyl](methyl)amino}-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 62% yield from Preparation 197daccording to the procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ1.60-1.79 (4H, m), 2.0-2.65 (2H, m), 2.98-3.02 (1H, m), 3.15 (3H, s),3.30 (3H, s), 3.38-3.54 (2H, m), 3.65 (2H, s), 4.06 (2H, s), 6.51-6.58(2H, m), 6.91 (2H, d, J=8.0 Hz), 7.00 (2H, d, J=7.8 Hz), 7.12 (1H, d,J=8.3 Hz), 7.56 (1H, br s), 7.82 (1H, br s), 7.84 (1H, br s), 8.32 (1H,br s), 13.4 (1H, br s). [M+H] Calc'd for C₂₇H₃₁N₃O₄, 462; Found, 462.

Preparation 198a: Methyl3-({[(4R)-7-(1-phenylethenyl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

To a solution of4,4,5,5-tetramethyl-2-(1-phenyl-vinyl)-[1,3,2]dioxaborolane (612 mg,2.66 mmol), S-Phos (55 mg, 0.13 mmol), Pd(OAc)₂ (15 mg, 0.0665 mmol) andK₃PO₄ (708 mg, 3.33 mmol) in ACN/H₂O (30 mL/10 mL) was added Preparation126b (500 mg, 1.33 mmol). The reaction mixture was stirred at 120° C.under N₂ overnight. The solvent was removed by vacuum, and the residuewas purified by silica gel chromatography (PE:EtOAc=3:1) to give 200 mg(38%) of the title compound. [M+H] Calc'd for C₂₅H₂₄N₂O₃, 401; Found,401.

Preparation 198b: Methyl3-({[(4R)-7-(1-phenylethyl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

10% Pd/C (20 mg) was added to a solution of Preparation 198a (0.1 g,0.25 mmol) in EtOH (15 mL) under N₂ at r.t. After stirring under 50 psiof H₂ overnight, the reaction mixture was filtered through Celite andconcentrated. The residue was purified by prep-HPLC to give 50 mg (50%)of the title compound as a brown oil. [M+H] Calc'd for C₂₅H₂₆N₂O₃, 403;Found, 403.

Example 198:3-({[(4R)-7-(1-phenylethyl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 83% yield from Preparation 198baccording to the procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ1.52 (3H, d, J=7.2 Hz) 1.80-1.90 (1H, m), 1.91-1.99 (1H, m), 3.03-3.09(1H, m), 3.43-3.49 (1H, m), 3.62-3.68 (1H, m), 4.04 (1H, t, J=7.2 Hz),4.09-4.18 (2H, m), 6.64 (1H, s), 6.75 (1H, d, J=8.0 Hz), 7.14-7.29 (6H,m), 7.58 (1H, d, J=5.2 Hz), 7.84 (1H, d, J=5.2 Hz), 8.40 (1H, s). [M+H]Calc'd for C₂₄H₂₄N₂O₃, 389; Found, 389.

Preparation 199a: 5-isopropyl-N-methylpyridin-2-amine

A solution of 5-isopropyl-pyridin-2-ylamine (0.5 g, 3.67 mmol) in dryTHF was purged with N₂ and cooled to −78° C. n-BuLi (1.62 mL, 4.04 mmol)was added dropwise. The reaction was stirred at 0° C. for 0.5 h, andthen iodomethane (0.25 mL, 4.04 mmol) was added dropwise. The resultingmixture was stirred overnight while warming to r.t. Water (20 mL) wasadded, and the mixture was extracted with EtOAc. The organic layer wasdried over Na₂SO₄, concentrated, and purified by silica gelchromatography (10% to 30% EtOAc in PE) to give 200 mg (36%) of thetitle compound as a brown oil. [M+H] Calc'd for C₉H₁₄N₂, 151; Found,151.

Preparation 199b: Methyl3-({[(4R)-7-{methyl[5-(propan-2-yl)pyridin-2-yl]amino}-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 65% yield from Preparation 126b and5-isopropyl-N-methylpyridin-2-amine according to the general procedureoutlined for Preparation 126c. [M+H] Calc'd for C₂₆H₃₀N₄O₃, 447; Found,447.

Example 199:3-({[(4R)-7-{methyl[5-(propan-2-yl)pyridin-2-yl]amino}-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 82% yield from Preparation 199baccording to the procedure for Example 1. ¹H NMR (300 MHz, DMSO-d₆): δ1.16 (6H, d, J=7.2 Hz), 1.85-1.93 (1H, m), 1.95-2.06 (1H, m), 2.73-2.84(1H, m), 3.09-3.16 (1H, m), 3.32 (3H, s), 3.48-3.56 (1H, m), 3.69-3.75(1H, m), 4.12-4.26 (2H, m), 6.57 (1H, d, J=8.1 Hz), 6.64 (1H, d, J=2.4Hz), 6.74 (1H, dd, J=8.1 Hz, 1.8 Hz), 7.32 (1H, d, J=8.4 Hz), 7.36 (1H,dd, J=8.4 Hz, 2.4 Hz), 7.57 (1H, d, J=5.1 Hz), 7.85 (1H, d, J=5.1 Hz),8.04 (1H, d, J=1.8 Hz), 8.42 (1H, s). [M+H] Calc'd for C₂₅H₂₈N₄O₃, 433;Found, 433.

Preparation 200a: Methyl3-({[(1R)-6-{methyl[4-(trifluoromethanesulfonyloxy)phenyl]amino}-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

To a solution of Preparation 165c (576 mg, 1.37 mmol) and pyridine (217mg, 2.75 mmol) in THF (10 mL) was added Tf₂O (407 mg, 1.44 mmol) slowlyat 0° C. The mixture was stirred at rt for 2 h. The mixture wasconcentrated and purified by silica gel chromatography (PE:EtOAc=2:1) togive 553 mg (73%) of the title compound as a yellow oil. [M+H] Calc'dfor C₂₆H₂₆F₃N₃O₅S, 550; Found, 550.

Preparation 200b: Methyl3-({[(1R)-6-[(4-{3-[(tert-butyldimethylsilyl)oxy]azetidin-1-yl}phenyl)(methyl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 55% yield from Preparation 200a and3-[(tert-butyldimethylsilanyl)oxy]azetidine according to the procedurefor Preparation 126c. [M+H] Calc'd for C₃₄H₄₆N₄O₃Si, 587; Found, 587.

Preparation 200c: Methyl3-({[(1R)-6-{[4-(3-hydroxyazetidin-1-yl)phenyl](methyl)amino}-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 89% yield from Preparation 200baccording to the procedure for Preparation 165c. [M+H] Calc'd forC₂₈H₃₂N₄O₃, 473; Found, 473.

Example 200:3-({[(1R)-6-{[4-(3-hydroxyazetidin-1-yl)phenyl](methyl)amino}-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 95% yield from Preparation 200caccording to the procedure for Example 1. ¹H NMR (300 MHz, DMSO-d₆): δ1.58-1.79 (4H, m), 2.56-2.60 (2H, m), 2.92-2.95 (1H, m), 3.09 (3H, s)3.26-3.32 (1H, m), 3.35-3.58 (4H, m), 4.02 (2H, t, J=6.6 Hz), 4.50-4.54(1H, m), 6.39-6.45 (4H, m), 6.92 (2H, d, J=6.0 Hz), 7.05 (1H, d, J=8.4Hz), 7.54 (1H, d, J=5.1 Hz), 7.78 (1H, d, J=4.8 Hz), 8.26 (1H, s). [M+H]Calc'd for C₂₇H₃₀N₄O₃, 459; Found, 459.

Preparation 201a: Methyl3-({[(4R)-7-{[4-(3,6-dihydro-2H-pyran-4-yl)phenyl](methyl)amino}-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 49% yield from Preparation 126b andPreparation 174a according to the general procedure outlined forPreparation 126c. [M+H] Calc'd for C₂₉H₃₁N₃O₄, 486; Found, 486.

Example 201:3-({[(4R)-7-{[4-(3,6-dihydro-2H-pyran-4-yl)phenyl](methyl)amino}-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 83% yield from Preparation 201aaccording to the procedure for Example 1. ¹H NMR (300 MHz, DMSO-d₆): δ1.86-1.98 (2H, m), 2.38-2.40 (2H, m), 3.03-3.08 (1H, m), 3.19 (3H, s),3.42-3.50 (1H, m), 3.63-3.68 (1H, m), 3.77-3.80 (2H, m), 4.11-4.19 (4H,m), 6.12 (1H, m), 6.39 (1H, d, J=2.1 Hz), 6.50-6.53 (1H, m), 6.93 (2H,d, J=8.7 Hz), 7.18 (1H, d, J=8.1 Hz), 7.33 (2H, d, J=8.1 Hz), 7.55 (1H,d, J=4.8 Hz), 7.82 (1H, d, J=5.1 Hz), 8.37 (1H, s). [M+H] Calc'd forC₂₈H₂₉N₃O₄, 472; Found, 472.

Preparation 202a: Methyl3-({[(4R)-7-{methyl[4-(oxan-4-yl)phenyl]amino}-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 42% yield from Preparation 126b andPreparation 175a according to the general procedure outlined forPreparation 126c. [M+H] Calc'd for C₂₉H₃₃N₃O₄, 488; Found, 488.

Example 202:3-({[(4R)-7-{methyl[4-(oxan-4-yl)phenyl]amino}-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 96% yield from Preparation 202aaccording to the procedure for Example 1. ¹H NMR (300 MHz, DMSO-d₆): δ1.59-1.67 (4H, m), 1.85-1.94 (2H, m), 2.67-2.70 (1H, m), 3.00-3.04 (1H,m), 3.22 (3H, s), 3.39-3.46 (3H, m), 3.59-3.65 (1H, m), 3.90-3.94 (2H,m), 4.09-4.14 (2H, m), 6.26 (1H, d, J=2.8 Hz), 6.27-6.43 (1H, m),6.94-6.97 (2H, m), 7.12-7.17 (3H, m), 7.54 (1H, d, J=4.8 Hz), 7.80 (1H,d, J=4.8 Hz), 8.34 (1H, s). [M+H] Calc'd for C₂₈H₃₁N₃O₄, 474; Found,474.

Preparation 203a: Tert-ButylN-{[(4R)-7-(1-phenylethenyl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}carbamate

The title compound was prepared in 87% yield from Preparation 18d and4,4,5,5-tetramethyl-2-(1-phenyl-vinyl)-[1,3,2]dioxaborolane according tothe procedure for Preparation 198a. Calc'd for C₂₂H₂₇NO₃, 309; Found,309.

Preparation 203b: Tert-ButylN-{[(4R)-7-(1-phenylcyclopropyl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}carbamate

A solution of Preparation 203a (0.2 g, 0.548 mmol) in DCE (5 mL) waspurged with N₂ and cooled to 0° C. Diethyl zinc (3.3 mL, 3.3 mmol) wasadded to the reaction mixture dropwise. After stirring for 10 min,diiodomethane (1.76 g, 6.576 mmol) was added dropwise. The reactionmixture was stirred overnight while warming to r.t. Water (10 mL) wasadded, and the mixture was extracted with EtOAc. The organic layer wasdried (Na₂SO₄) and concentrated. The residue was purified by silica gelchromatography (PE:EtOAc=10:1) to give 13 mg (6%) of the title compoundas a brown oil. Calc'd for C₂₄H₂₉NO₃, 323; Found, 323.

Preparation 203c:[(4R)-7-(1-phenylcyclopropyl)-3,4-dihydro-2H-1-benzopyran-4-yl]methanamine

A mixture of Preparation 203b (30 mg) in HCl solution (2.0 M in EtOAc,10 mL) was stirred for 2 h at r.t. The solution was concentrated andused for next reaction without further purification. Calc'd forC₁₉H₂₁NO, 263; Found, 263.

Preparation 203d: Methyl3-({[(4R)-7-(1-phenylcyclopropyl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 40% yield from Preparation 203caccording to the procedure for Preparation 4d. [M+H] Calc'd forC₂₆H₂₆N₂O₃, 415; Found, 415.

Example 203:3-({[(4R)-7-(1-phenylcyclopropyl)-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 63% yield from Preparation 203daccording to the procedure for Example 1. ¹H NMR (300 MHz, DMSO-d₆): δ1.19 (4H, s), 1.80-1.87 (1H, m), 1.91-2.01 (1H, m), 3.04-3.09 (1H, m)3.42-3.51 (1H, m), 3.62-3.69 (1H, m), 4.08-4.20 (2H, m), 6.57 (1H, d,J=1.8 Hz), 6.70 (1H, dd, J=7.8 Hz, 1.8 Hz), 7.15-7.30 (6H, m), 7.57 (1H,d, J=5.1 Hz), 7.84 (1H, d, J=5.1 Hz), 8.40 (1H, s). [M+H] Calc'd forC₂₅H₂₄N₂O₃, 401; Found, 401.

Preparation 204a:N-methyl-4-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)aniline

The title compound was prepared in 37% yield, using1-methyl-1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester,according to the general procedure for the preparation of Preparation174a. [M+H] Calc'd for C₁₃H₁₈N₂, 203; Found, 203.

Preparation 204b: Methyl3-({[(4R)-7-{methyl[4-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl]amino}-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 20% yield from Preparation 126b andPreparation 204a according to the general procedure outlined forPreparation 126c. [M+H] Calc'd for C₃₀H₃₄N₄O₃, 499; Found, 499.

Example 204:3-({[(4R)-7-{methyl[4-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl]amino}-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 16% yield from Preparation 204baccording to the procedure for Example 1. ¹H NMR (300 MHz, DMSO-d₆): δ1.82-1.98 (m, 2H), 2.77-3.04 (m, 6H), 3.04-3.08 (m, 1H), 3.20 (s, 3H),3.30-3.76 (m, 5H), 4.11-4.16 (m, 2H), 6.05 (s, 1H), 6.43 (d, 1H, J=2.1Hz), 6.55 (dd, 1H, J=2.1 Hz, 8.1 Hz), 6.91 (d, 2H, J=8.7 Hz), 7.21 (d,1H, J=7.8 Hz), 7.35 (d, 2H, J=8.7 Hz), 7.55 (d, 1H, J=5.4 Hz), 7.81 (d,1H, J=4.8 Hz), 8.36 (s, 1H). [M+H] Calc'd for C₂₉H₃₂N₄O₃, 485; Found,485.

Preparation 205a: N-methyl-4-(1-methylpiperidin-4-yl)aniline

The title compound was prepared in 90% yield from Preparation 204aaccording to the general procedure for Preparation 175a. [M+H] Calc'dfor C₁₃H₂₀N₂, 205; Found, 205.

Preparation 205b: Methyl3-({[(4R)-7-{methyl[4-(1-methylpiperidin-4-yl)phenyl]amino}-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 18% yield from Preparation 126b andPreparation 205a according to the general procedure outlined forPreparation 126c. [M+H] Calc'd for C₃₀H₃₆N₄O₃, 501; Found, 501.

Example 205:3-({[(4R)-7-{methyl[4-(1-methylpiperidin-4-yl)phenyl]amino}-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 14% yield from Preparation 205baccording to the procedure for Example 1. ¹H NMR (300 MHz, DMSO-d₆): δ1.90-1.93 (m, 6H), 2.72 (s, 3H), 3.00-3.03 (m, 3H), 3.16 (s, 3H),3.39-3.61 (m, 5H), 4.09-4.10 (m, 2H), 6.29 (d, 1H, J=2.1 Hz), 6.43 (dd,1H, J=2.1, 8.7 Hz), 6.96 (d, 2H, J=8.4 Hz), 7.14 (d, 3H, J=8.7 Hz), 7.56(d, 1H, J=5.4 Hz), 7.82 (d, 1H, J=5.1 Hz), 8.36 (s, 1H). [M+H] Calc'dfor C₂₉H₃₄N₄O₃, 487; Found, 487.

Preparation 206a: N,3,4-trimethylaniline

The title compound was prepared in 33% overall yield from3,4-dimethylaniline according to the general procedure outlined forPreparation 127a. [M+H] Calc'd for C₉H₁₃N, 136; Found, 136.

Preparation 206b: Methyl3-({[(4R)-7-[(3,4-dimethylphenyl)(methyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 43% yield from Preparation 126b andN,3,4-trimethylaniline according to the general procedure outlined forPreparation 126c. [M+H] Calc'd for C₂₆H₂₉N₃O₃, 432; Found, 432.

Example 206:3-({[(4R)-7-[(3,4-dimethylphenyl)(methyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 87% yield from Preparation 206baccording to the procedure for Example 1. ¹H NMR (300 MHz, DMSO-d₆): δ1.79-1.97 (2H, m), 2.16 (6H, s) 2.99-3.03 (1H, m), 3.13 (3H, s),3.39-3.48 (1H, m), 3.59-3.65 (1H, m), 4.05-4.17 (2H, m), 6.19 (1H, d,J=2.4 Hz), 6.32-6.36 (1H, m), 6.75-6.79 (1H, m), 6.85 (1H, d, J=1.8 Hz),7.03-7.10 (2H, m), 7.54 (1H, d, J=4.8 Hz), 7.82 (1H, d, J=4.8 Hz), 8.36(1H, s). [M+H] Calc'd for C₂₅H₂₇N₃O₃, 418; Found, 418.

Preparation 207a: 4-(2-((tert-butyldimethylsilyl)oxy)ethyl)aniline

The title compound was prepared in quantitative yield from2-(4-aminophenyl)ethan-1-ol according to the procedure for Preparation165a. [M+H] Calc'd for C₁₄H₂₅NOSi, 252; Found, 252.

Preparation 207b:4-(2-((tert-butyldimethylsilyl)oxy)ethyl)-N-methylaniline

The title compound was prepared in 49% overall yield from4-(2-((tert-butyldimethylsilyl)oxy)ethyl)aniline according to thegeneral procedure outlined for Preparation 127a. [M+H] Calc'd forC₁₅H₂₇NOSi, 266; Found, 266.

Preparation 207c: Methyl3-({[(4R)-7-[(4-{2-[(tert-butyldimethylsilyl)oxy]ethyl}phenyl)-(methyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 39% yield from Preparation 126b andPreparation 207b according to the general procedure outlined forPreparation 126c. [M+H] Calc'd for C₃₂H₄₃N₃O₄Si, 562; Found, 562.

Preparation 207d: Methyl3-({[(4R)-7-{[4-(2-hydroxyethyl)phenyl](methyl)amino}-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 80% yield from Preparation 207caccording to the procedure for Preparation 165c. [M+H] Calc'd forC₂₆H₂₉N₃O₄, 448; Found, 448.

Example 207:3-({[(4R)-7-{[4-(2-hydroxyethyl)phenyl](methyl)amino}-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 95% yield from Preparation 207daccording to the procedure for Example 1. ¹H NMR (300 MHz, DMSO-d₆): δ1.79-1.95 (2H, m), 2.65 (2H, t, J=7.2 Hz), 3.01-3.04 (1H, m), 3.12 (3H,s) 3.43-3.48 (1H, m), 3.53-3.66 (3H, m), 4.08-4.15 (2H, m), 6.24 (1H, d,J=2.4 Hz), 6.37-6.40 (1H, m), 6.92-6.95 (2H, m), 7.11-7.13 (3H, m), 7.56(1H, d, J=5.1 Hz), 7.83 (1H, d, J=4.8 Hz), 8.38 (1H, s). [M+H] Calc'dfor C₂₅H₂₇N₃O₄, 434; Found, 434.

Preparation 208a: N-methyl-4-propylaniline

The title compound was prepared in 95% overall yield from4-propylaniline according to the general procedure outlined forPreparation 127a. [M+H] Calc'd for C₁₀H₁₅N, 150; Found, 150.

Preparation 208b: Methyl3-({[(4R)-7-[methyl(4-propylphenyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 24% yield from Preparation 126b andN-methyl-4-propylaniline according to the general procedure outlined forPreparation 126c. [M+H] Calc'd for C₂₇H₃₁N₃O₃, 446; Found, 446.

Example 208:3-({[(4R)-7-[methyl(4-propylphenyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 88% yield from Preparation 208baccording to the procedure for Example 1. ¹H NMR (300 MHz, DMSO-d₆): δ0.89 (3H, t, J=7.2 Hz), 1.50-1.63 (2H, m), 1.81-1.87 (1H, m), 1.91-2.01(1H, m), 2.99-3.12 (1H, m), 3.17 (3H, s), 3.40-3.50 (3H, m), 3.61-3.68(1H, m), 4.06-4.21 (2H, m), 6.25 (1H, d, J=2.4 Hz), 6.40 (1H, dd, J=8.4Hz, 2.4 Hz), 6.96 (2H, d, J=8.4 Hz), 7.11 (2H, d, J=8.4 Hz), 7.13 (1H,d, J=8.4 Hz), 7.56 (1H, d, J=5.1 Hz), 7.84 (1H, d, J=5.1 Hz), 8.39 (1H,s). [M+H] Calc'd for C₂₆H₂₉N₃O₃, 432; Found, 432.

Preparation 209a: Tert-ButylN-{[(1R)-6-{[4-(cyclopropylmethoxy)phenyl](methyl)amino}-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}carbamate

The title compound was prepared in 66% yield from4-(cyclopropylmethoxy)-N-methylaniline and Preparation 6d according tothe general procedure outlined for Preparation 9a. [M+H] Calc'd forC₂₇H₃₆N₂O₃, 437; Found, 437.

Preparation 209b:(5R)-5-(aminomethyl)-N-[4-(cyclopropylmethoxy)phenyl]-N-methyl-5,6,7,8-tetrahydronaphthalen-2-amine

The title compound was prepared in quantitative yield from Preparation209a according to the procedure for Preparation 43b. [M+H] Calc'd forC₂₂H₂₈N₂O, 337; Found, 337.

Preparation 209c: Methyl3-({[(1R)-6-{[4-(cyclopropylmethoxy)phenyl](methyl)amino}-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 72% yield from Preparation 209baccording to the procedure for Preparation 4d. [M+H] Calc'd forC₂₉H₃₃N₃O₃, 472; Found, 472.

Example 209:3-({[(1R)-6-{[4-(cyclopropylmethoxy)phenyl](methyl)amino}-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 89% yield from Preparation 209caccording to the procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ0.24 (2H, s), 0.49 (2H, d, J=6.0 Hz), 1.11-1.17 (1H, m), 1.52-1.58 (1H,m), 1.68-1.75 (3H, m), 2.53-2.58 (2H, m), 2.90-2.95 (1H, s), 3.07 (3H,s), 3.25-3.46 (2H, m), 3.71 (2H, d, J=6.7 Hz), 6.43 (1H, s), 6.48 (1H,d, J=7.4 Hz), 6.81 (2H, d, J=8.4 Hz), 6.92 (2H, d, J=8.4 Hz), 7.04 (1H,d, J=8.2 Hz), 7.50 (1H, s), 7.74 (1H, s), 8.22 (1H, s). [M+H] Calc'd forC₂₈H₃₁N₃O₃, 458; Found, 458.

Preparation 210a: 4-isopropoxy-N-methylaniline

The title compound was prepared in 96% overall yield from4-isopropoxyaniline according to the general procedure outlined forPreparation 127a. [M+H] Calc'd for C₁₀H₁₅NO, 166; Found, 166.

Preparation 210b: Methyl3-({[(4R)-7-{methyl[4-(propan-2-yloxy)phenyl]amino}-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 45% yield from Preparation 126b and4-isopropoxy-N-methylaniline according to the general procedure outlinedfor Preparation 126c. [M+H] Calc'd for C₂₇H₃₁N₃O₄, 462; Found, 462.

Example 210:3-({[(4R)-7-{methyl[4-(propan-2-yloxy)phenyl]amino}-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 78% yield from Preparation 210baccording to the procedure for Example 1. ¹H NMR (400 MHz, DMSO-d₆): δ1.26 (6H, d, J=6.0 Hz), 1.79-1.86 (1H, m), 1.91-2.01 (1H, m), 2.97-3.05(1H, m), 3.13 (3H, s), 3.40-3.46 (1H, m), 3.59-3.64 (1H, m), 4.05-4.17(2H, m), 4.50-4.60 (1H, m), 6.10 (1H, d, J=2.4 Hz), 6.26 (1H, dd, J=8.4Hz, 2.4 Hz), 6.89 (2H, d, J=8.4 Hz), 7.02 (2H, d, J=8.4 Hz), 7.08 (1H,d, J=8.4 Hz), 7.56 (1H, d, J=5.2 Hz), 7.83 (1H, d, J=5.2 Hz), 8.37 (1H,s). [M+H] Calc'd for C₂₆H₂₉N₃O₄, 448; Found, 448.

Preparation 211a: 1-(cyclopropylmethoxy)-4-nitrobenzene

4-Nitrophenol (5.0 g, 35.9 mmol) was added to a suspension of(bromomethyl)cyclopropane (10.7 g, 79.07 mmol) and K₂CO₃ (19.9 g, 143.76mmol) in DMF (80 mL), and the reaction was stirred at 40° C. overnight.The reaction mixture was diluted with water (300 mL) and extracted withEtOAc (100 mL×3). Organics were washed with brine (50 mL), dried(Na₂SO₄), and concentrated. The residue was purified by silica gelchromatography (0-5% EtOAc/PE) to give 6.77 g (98%) of the titlecompound as a colorless oil. [M+H] Calc'd for C₁₀H₁₁NO₃, 194; Found,194.

Preparation 211b: 4-(cyclopropylmethoxy)aniline

10% Pd/C (680 mg) was added to a solution of Preparation 211a (6.77 g,35.1 mmol) in EtOAc (70 mL) under N₂, and the reaction mixture stirredunder H₂ at r.t. overnight. The reaction mixture was filtered throughCelite and concentrated to give 5.72 g (100%) of the title compound as abrown oil. [M+H] Calc'd for C₁₀H₁₃NO, 164; Found, 164.

Preparation 211c: 4-(cyclopropylmethoxy)-N-methylaniline

The title compound was prepared in 91% overall yield from Preparation211b according to the general procedure outlined for Preparation 127a.[M+H] Calc'd for C₁₁H₁₅NO, 178; Found, 178.

Preparation 211d: Methyl3-({[(4R)-7-{[4-(cyclopropylmethoxy)phenyl](methyl)amino}-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 55% yield from Preparation 126b andPreparation 211c according to the general procedure outlined forPreparation 126c. [M+H] Calc'd for C₂₈H₃₁N₃O₄, 474; Found, 474.

Example 211:3-({[(4R)-7-{[4-(cyclopropylmethoxy)phenyl](methyl)amino}-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 89% yield from Preparation 210baccording to the procedure for Example 1. ¹H NMR (300 MHz, DMSO-d₆): δ0.29-0.34 (2H, m), 0.53-0.60 (2H, m), 1.16-1.24 (1H, m), 1.77-2.01 (2H,m), 2.96-3.05 (1H, m), 3.13 (3H, s), 3.39-3.47 (1H, m), 3.58-3.65 (1H,m), 3.79 (2H, d, J=6.9 Hz), 4.03-4.19 (2H, m), 6.09 (1H, d, J=2.4 Hz),6.25 (1H, dd, J=8.4 Hz, 2.4 Hz), 6.91 (2H, d, J=9.0 Hz), 7.03 (2H, d,J=9.0 Hz), 7.07 (1H, d, J=8.4 Hz), 7.56 (1H, d, J=5.1 Hz), 7.83 (1H, d,J=5.1 Hz), 8.37 (1H, s). [M+H] Calc'd for C₂₇H₂₉N₃O₄, 460; Found, 460.

Preparation 212a: 1-nitro-4-propoxybenzene

The title compound was prepared in 98% yield according to the procedurefor Preparation 211a. [M+H] Calc'd for C₉H₁₁NO₃, 182; Found, 182.

Preparation 212b: 4-propoxyaniline

The title compound was prepared in 100% yield from Preparation 212aaccording to the procedure for Preparation 211b. [M+H] Calc'd forC₉H₁₃NO, 152; Found, 152.

Preparation 212c: N-methyl-4-propoxyaniline

The title compound was prepared in 86% overall yield from4-propoxyaniline according to the general procedure outlined forPreparation 127a. [M+H] Calc'd for C₁₀H₁₅NO, 166; Found, 166.

Preparation 212d: Methyl3-({[(4R)-7-[methyl(4-propoxyphenyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 56% yield from Preparation 126b andPreparation 212c according to the general procedure outlined forPreparation 126c. [M+H] Calc'd for C₂₈H₃₁N₃O₄, 462; Found, 462.

Example 212:3-({[(4R)-7-[methyl(4-propoxyphenyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 88% yield from Preparation 212daccording to the procedure for Example 1. ¹H NMR (300 MHz, DMSO-d₆): δ0.95 (3H, t, J=7.5 Hz), 1.68-1.96 (4H, m), 2.99-3.03 (1H, m), 3.12 (3H,s), 3.40-3.47 (1H, m), 3.59-3.65 (1H, m), 3.90 (2H, t, J=6.3 Hz),4.09-4.14 (2H, m), 6.10 (1H, s), 6.25 (1H, dd, J=8.4 Hz, 1.5 Hz),6.89-6.92 (2H, m), 7.02-7.08 (3H, m), 7.59 (1H, d, J=5.1 Hz), 7.84 (1H,d, J=4.8 Hz), 8.39 (1H, s). [M+H] Calc'd for C₂₆H₂₉N₃O₄, 448; Found,448.

Preparation 213a: 4-cyclopropoxy-N-methylaniline

The title compound was prepared in 17% yield from1-bromo-4-cyclopropoxybenzene according to the procedure for Preparation187a. [M+H] Calc'd for C₁₀H₁₃NO, 164; Found, 164.

Preparation 213b: methyl3-({[(4R)-7-[(4-cyclopropoxyphenyl)(methyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 22% yield from Preparation 126b andPreparation 213a according to the general procedure outlined forPreparation 126c. [M+H] Calc'd for C₂₇H₂₉N₃O₄, 460; Found, 460.

Example 213:3-({[(4R)-7-[(4-cyclopropoxyphenyl)(methyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 59% yield from Preparation 213baccording to the procedure for Example 1. ¹H NMR (300 MHz, DMSO-d₆): δ0.62-0.68 (2H, m), 0.73-0.80 (2H, m), 1.77-2.01 (2H, m), 2.96-3.05 (1H,m), 3.14 (3H, s), 3.39-3.47 (1H, m), 3.59-3.65 (1H, m), 3.78-3.85 (1H,m), 4.04-4.19 (2H, m), 6.11 (1H, d, J=1.5 Hz), 6.31 (1H, dd, J=8.4 Hz,1.5 Hz), 7.01-7.10 (5H, m), 7.56 (1H, d, J=4.8 Hz), 7.83 (1H, d, J=4.8Hz), 8.37 (1H, s). [M+H] Calc'd for C₂₆H₂₇N₃O₄, 446; Found, 446.

Preparation 214a: N-methyl-4-(2,2,2-trifluoroethoxy)aniline

The title compound was prepared in 98% overall yield from4-(2,2,2-trifluoroethoxy)aniline according to the general procedureoutlined for Preparation 127a. [M+H] Calc'd for C₉H₁₀F₃NO, 206; Found,206.

Preparation 214b: Methyl3-({[(4R)-7-{methyl[4-(2,2,2-trifluoroethoxy)phenyl]amino}-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 35% yield from Preparation 126b andPreparation 214a according to the general procedure outlined forPreparation 126c. [M+H] Calc'd for C₂₆H₂₆F₃N₃O₄, 502; Found, 502.

Example 214:3-({[(4R)-7-{methyl[4-(2,2,2-trifluoroethoxy)phenyl]amino}-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 62% yield from Preparation 214baccording to the procedure for Example 1. ¹H NMR (300 MHz, DMSO-d₆): δ1.78-2.03 (2H, m), 2.98-3.07 (1H, m), 3.15 (3H, s), 3.41-3.49 (1H, m),3.60-3.67 (1H, m), 4.05-4.20 (2H, m), 4.73 (2H, q, J=9.0 Hz), 6.17 (1H,d, J=2.1 Hz), 6.31 (1H, dd, J=8.4 Hz, 2.1 Hz), 7.01-7.12 (5H, m), 7.56(1H, d, J=4.8 Hz), 7.84 (1H, d, J=4.8 Hz), 8.39 (1H, s). [M+H] Calc'dfor C₂₅H₂₄F₃N₃O₄, 488; Found, 488.

Preparation 215a: cyclopropyl(4-(methylamino)phenyl)methanone

The title compound was prepared in 57% yield from 4-bromophenylcyclopropyl ketone according to the procedure for Preparation 187a.[M+H] Calc'd for C₁₁H₁₃NO, 176; Found, 176.

Preparation 215b: 4-(cyclopropylmethyl)-N-methylaniline

Preparation 215a (0.5 g, 2.85 mmol), hydrazine monohydrate (0.3 ml) andpotassium hydroxide (0.4 g) were added to ethylene glycol (5 ml), andthe mixture was heated to reflux for 1 h. The hydrazine monohydrate andwater were then boiled off by heating open for 2 h. The reaction mixturewas cooled and partitioned between water (20 ml) and ethyl acetate (30ml), and the organic layer was separated. The aqueous layer wasextracted with ethyl acetate (30 ml) and the combined organic phaseswere washed with water (15 ml) and brine (15 ml), dried (Na₂SO₄), andconcentrated. The residue was purified by silica gel chromatography(0-10% EtOAc/PE) to give 0.22 g (48%) of the title compound as acolorless oil. [M+H] Calc'd for C₁₁H₁₅N, 162; Found, 162.

Preparation 215c: Methyl3-({[(4R)-7-{[4-(cyclopropylmethyl)phenyl](methyl)amino}-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 40% yield from Preparation 126b andPreparation 215b according to the general procedure outlined forPreparation 126c. [M+H] Calc'd for C₂₈H₃₁N₃O₃, 458; Found, 458.

Example 215:3-({[(4R)-7-{[4-(cyclopropylmethyl)phenyl](methyl)amino}-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 85% yield from Preparation 215caccording to the procedure for Example 1. ¹H NMR (300 MHz, DMSO-d₆): δ0.15-0.21 (2H, m), 0.43-0.50 (2H, m), 0.90-1.01 (1H, m), 1.80-1.90 (1H,m), 1.91-2.03 (1H, m), 2.45 (2H, d, J=7.2 Hz), 3.01-3.07 (1H, m), 3.18(3H, s), 3.41-3.50 (1H, m), 3.61-3.68 (1H, m), 4.06-4.21 (2H, m), 6.26(1H, d, J=2.1 Hz), 6.41 (1H, dd, J=8.4 Hz, 2.1 Hz), 6.97 (2H, d, J=7.8Hz), 7.14 (1H, d, J=8.4 Hz), 7.19 (2H, d, J=8.7 Hz), 7.56 (1H, d, J=4.8Hz), 7.56 (1H, d, J=4.8 Hz), 8.38 (1H, s). [M+H] Calc'd for C₂₇H₂₉N₃O₃,444; Found, 444.

Preparation 216a: Methyl3-({[(4R)-7-[(4-cyclopropanecarbonylphenyl)(methyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 58% yield from Preparation 126b andPreparation 215a according to the general procedure outlined forPreparation 126c. [M+H] Calc'd for C₂₈H₂₉N₃O₄, 472; Found, 472.

Example 216:3-({[(4R)-7-[(4-cyclopropanecarbonylphenyl)(methyl)amino]-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 92% yield from Preparation 215caccording to the procedure for Example 1. ¹H NMR (300 MHz, DMSO-d₆): δ0.92-0.95 (4H, m), 1.88-2.07 (2H, m), 2.72-2.82 (1H, m), 3.11-3.20 (1H,m), 3.30 (3H, s), 3.49-3.57 (1H, m), 3.70-3.76 (1H, m), 4.15-4.27 (2H,m), 6.67 (1H, s), 6.75 (1H, d, J=7.5 Hz), 6.81 (2H, d, J=8.4 Hz), 7.38(1H, d, J=8.4 Hz), 7.58 (1H, d, J=4.8 Hz), 7.85 (1H, d, J=4.8 Hz), 7.89(2H, d, J=8.4 Hz), 8.41 (1H, s). [M+H] Calc'd for C₂₇H₂₇N₃O₄, 458;Found, 458.

Preparation 217a: (6-bromo-1H-inden-3-yl)methanamine, Hydrochloride

To a solution of 5-bromo-1-indanone (10.0 g, 47.4 mmol) and ZnI₂ (100mg) in toluene (100 mL) was added TMSCN (15.0 mL, 94.8 mmol) at rt. Thesolution was heated at 60° C. overnight. The reaction was cooled to rt,and THF (50 mL) was added. LAH (40.0 mL, 2.4 M, 94.8 mmol) was addeddropwise at rt, and the reaction was heated at 40° C. for 3 h. EtOAc (50mL) was added at rt, the reaction mixture was stirred for 30 min. Water(10 mL) was added, and the reaction stirred for 30 min and then wasdried (Na₂SO₄), filtered, and concentrated in vacuo to a brown oil.

To a solution of this brown oil in toluene (50 mL) was added HCl/dioxane(30 mL, 1.0 M), and the reaction was stirred at reflux for 10 min. Thereaction was cooled to rt, and the solid was collected by filtration togive 8.6 g (70%) of the crude title compound as a yellow solid. [M+H]Calc'd for C₁₀H₁₀BrN, 224, 226; Found, 224, 226.

Preparation 217b: (5-bromo-2,3-dihydro-1H-inden-1-yl)methanamine

To a solution of Preparation 217a (3.0 g, 11.5 mmol) in MeOH (50 mL) andAcOH (5 mL) was added Raney Ni (300 mg) at rt. The mixture was stirredat 50° C. overnight under 50 psi of H₂. After filtration, the solventwas removed under vacuum. The residue was diluted with EtOAc andbasified to pH 8 with K₂CO₃. The organic layer was separated, washedwith brine, dried (Na₂SO₄) and concentrated to give 2.2 g (85%) of thetitle compound as a brown oil. [M+H] Calc'd for C₁₀H₁₂BrN, 226, 228;Found, 226, 228.

Preparation 217c: Methyl3-{[(5-bromo-2,3-dihydro-1H-inden-1-yl)methyl]amino}pyridine-4-carboxylate

To a suspension of Preparation 217b (500 mg, 2.2 mmol), methyl3-bromoisonicotinate (717 mg, 3.3 mmol), Xantphos (192 mg, 0.3 mmol) andCs₂CO₃ (1.0 g, 3.1 mmol) in toluene (30 mL) was added Pd₂dba₃ (102 mg,0.1 mmol) at rt under N₂. The reaction was stirred at reflux overnight.After filtration, the solvent was removed in vacuo, and the residue waspurified by silica gel chromatography (PE:EtOAc=5:1) to give 380 mg(48%) of the title compound as a yellow oil. [M+H] Calc'd forC₁₇H₁₇BrN₂O₂, 360, 362; Found, 360, 362.

Preparation 217d: Methyl3-({[(1S)-5-[methyl(phenyl)amino]-2,3-dihydro-1H-inden-1-yl]methyl}amino)pyridine-4-carboxylate;and Preparation 217e: Methyl3-({[(1R)-5-[methyl(phenyl)amino]-2,3-dihydro-1H-inden-1-yl]methyl}amino)pyridine-4-carboxylate

To a suspension of Preparation 217c (380 mg, 1.05 mmol), N-methylaniline (135 mg, 1.26 mmol), Xantphos (91 mg, 0.16 mmol) and Cs₂CO₃ (479mg, 1.47 mmol) in toluene (30 mL) was added Pd₂dba₃ (48 mg, 0.053 mmol)at rt under N₂. The reaction was stirred at reflux overnight. Afterfiltration, the solvent was removed in vacuo, and the residue waspurified by silica gel chromatography (PE:EtOAc=5:1) to give 150 mg(37%) of the product racemate as a yellow oil. [M+H] Calc'd forC₂₄H₂₅N₃O₂, 388; Found, 388.

Separation by chiral prep-HPLC (Column: Chiralcel: IC 5 um 4.6*250 mm,Mobile phase: Hex:EtOH=80:20, F: 1.0 mL/min, W: 230 nm, T: ambient) gave60 mg (40%) of Preparation 217d (10.726 min) and 50 mg (33%) ofPreparation 217e (13.051 min), each as a yellow oil.

Example 217:3-({[(1S)-5-[methyl(phenyl)amino]-2,3-dihydro-1H-inden-1-yl]methyl}amino)pyridine-4-carboxylicAcid

To a solution of Preparation 217d (40 mg, 0.10 mmol) in THF (5 mL) andH₂O (5 mL) was added LiOH.H₂O (4 mg, 0.20 mmol) at rt, and the reactionwas stirred for 2 h. THF was removed in vacuo, the residue was acidifiedto pH=5 with 1.0 N aqueous HCl solution. The precipitate was collectedby filtration to give 30 mg (77%) of the title compound as a yellowsolid. ¹H NMR (300 MHz, DMSO-d₆): δ 1.79-1.86 (1H, m), 2.22-2.28 (1H,m), 2.74-2.82 (1H, m), 2.87-2.94 (1H, m), 3.20 (3H, s), 3.27-3.42 (2H,m), 3.59-3.62 (1H, m), 6.81-6.92 (5H, m), 7.17-7.27 (3H, m), 7.54 (1H,d, J=4.8 Hz), 7.81 (1H, d, J=5.1 Hz), 8.32 (1H, s). [M+H] Calc'd forC₂₃H₂₃N₃O₂, 374; Found, 374.

Example 218:3-({[(1R)-5-[methyl(phenyl)amino]-2,3-dihydro-1H-inden-1-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 90% yield from Preparation 217eaccording to the procedure for Example 217. ¹H NMR (300 MHz, DMSO-d₆): δ1.79-1.86 (1H, m), 2.22-2.28 (1H, m), 2.74-2.82 (1H, m), 2.87-2.94 (1H,m), 3.20 (3H, s), 3.27-3.42 (2H, m), 3.59-3.62 (1H, m), 6.81-6.92 (5H,m), 7.17-7.27 (3H, m), 7.54 (1H, d, J=4.8 Hz), 7.81 (1H, d, J=5.1 Hz),8.32 (1H, s). [M+H] Calc'd for C₂₃H₂₃N₃O₂, 374; Found, 374.

Preparation 219a: Methyl3-({[(1S)-5-[methyl(4-methylphenyl)amino]-2,3-dihydro-1H-inden-1-yl]methyl}amino)pyridine-4-carboxylate;and Preparation 219b: Methyl3-({[(1R)-5-[methyl(4-methylphenyl)amino]-2,3-dihydro-1H-inden-1-yl]methyl}amino)pyridine-4-carboxylate

The racemate of the title compounds was prepared in 42% yield fromPreparation 217c and N-methyl-p-toluidine according to the procedure forPreparation 217d and 217e. [M+H] Calc'd for C₂₅H₂₇N₃O₂, 402; Found, 402.

Separation by chiral prep-HPLC (Column: Chiralcel: IC 5 um 4.6*250 mm,Mobile phase: Hex:EtOH=60:40, F: 1.0 mL/min, W: 230 nm, T: ambient) gavePreparation 219a (6.536 min, 43% yield) and Preparation 219b (7.378 min,40% yield), each as a yellow oil.

Example 219:3-({[(1S)-5-[methyl(4-methylphenyl)amino]-2,3-dihydro-1H-inden-1-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 89% yield from Preparation 219baccording to the procedure for Example 217. ¹H NMR (300 MHz, DMSO-d₆): δ1.77-1.83 (1H, m), 2.16-2.28 (4H, m), 2.69-2.93 (2H, m), 3.16 (3H, s),3.29-3.39 (2H, m), 3.57-3.59 (1H, m), 6.70-6.73 (1H, m), 6.80-6.87 (3H,m), 7.05 (2H, d, J=8.1 Hz), 7.20 (1H, d, J=8.4 Hz), 7.54 (1H, d, J=5.1Hz), 7.81 (1H, d, J=5.1 Hz), 8.32 (1H, s). [M+H] Calc'd for C₂₄H₂₅N₃O₂,388; Found, 388.

Example 220:3-({[(1R)-5-[methyl(4-methylphenyl)amino]-2,3-dihydro-1H-inden-1-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 75% yield from Preparation 219aaccording to the procedure for Example 217. ¹H NMR (300 MHz, DMSO-d₆): δ1.77-1.83 (1H, m), 2.16-2.28 (4H, m), 2.69-2.93 (2H, m), 3.16 (3H, s),3.29-3.39 (2H, m), 3.57-3.59 (1H, m), 6.70-6.73 (1H, m), 6.80-6.87 (3H,m), 7.05 (2H, d, J=8.1 Hz), 7.20 (1H, d, J=8.4 Hz), 7.54 (1H, d, J=5.1Hz), 7.81 (1H, d, J=5.1 Hz), 8.32 (1H, s). [M+H] Calc'd for C₂₄H₂₅N₃O₂,388; Found, 388.

Preparation 221a: Methyl3-({[(1S)-5-{[4-(dimethylamino)phenyl](methyl)amino}-2,3-dihydro-1H-inden-1-yl]methyl}amino)pyridine-4-carboxylate;and Preparation 221b: Methyl3-({[(1R)-5-{[4-(dimethylamino)phenyl](methyl)amino}-2,3-dihydro-1H-inden-1-yl]methyl}amino)pyridine-4-carboxylate

The racemate of the title compounds was prepared in 34% yield fromPreparation 217c and 1-N,1-N,4-N-trimethylbenzene-1,4-diamine accordingto the procedure for Preparation 217d and 217e. [M+H] Calc'd forC₂₆H₃₀N₄O₂, 431; Found, 431.

Separation by chiral prep-HPLC (Column: Chiralcel: ID 5 um 4.6*250 mm,Mobile phase: Hex:IPA=50:50, W: 230 nm, T: 30° C.) gave Preparation 221a(10.573 min, 40% yield) and Preparation 221b (13.379 min, 42% yield),each as a yellow oil.

Example 221:3-({[(1S)-5-{[4-(dimethylamino)phenyl](methyl)amino}-2,3-dihydro-1H-inden-1-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 77% yield from Preparation 221aaccording to the procedure for Example 217. ¹H NMR (300 MHz, DMSO-d₆): δ1.74-1.80 (1H, m), 2.16-2.22 (1H, m), 2.65-3.31 (13H, m), 3.49-3.51 (1H,m), 6.46-7.14 (7H, m), 7.53 (1H, d, J=4.8 Hz), 7.80 (1H, d, J=4.8 Hz),8.29 (1H, s). [M+H] Calc'd for C₂₅H₂₆N₄O₂, 417; Found, 417.

Example 222:3-({[(1R)-5-{[4-(dimethylamino)phenyl](methyl)amino}-2,3-dihydro-1H-inden-1-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 78% yield from Preparation 221baccording to the procedure for Example 217. ¹H NMR (300 MHz, DMSO-d₆): δ1.74-1.80 (1H, m), 2.16-2.22 (1H, m), 2.65-3.31 (13H, m), 3.49-3.51 (1H,m), 6.46-7.14 (7H, m), 7.53 (1H, d, J=4.8 Hz), 7.80 (1H, d, J=4.8 Hz),8.29 (1H, s). [M+H] Calc'd for C₂₅H₂₆N₄O₂, 417; Found, 417.

Preparation 223a: Methyl3-({[(1S)-5-[(4-cyclopropylphenyl)(methyl)amino]-2,3-dihydro-1H-inden-1-yl]methyl}amino)pyridine-4-carboxylate;and Preparation 223b: Methyl3-({[(1R)-5-[(4-cyclopropylphenyl)(methyl)amino]-2,3-dihydro-1H-inden-1-yl]methyl}amino)pyridine-4-carboxylate

The racemate of the title compounds was prepared in 41% yield fromPreparation 217c and 4-cyclopropyl-N-methylaniline according to theprocedure for Preparation 217d and 217e. [M+H] Calc'd for C₂₇H₂₉N₃O₂,428; Found, 428.

Separation by chiral HPLC (Column: Chiralcel: ID 5 um 4.6*250 mm, Mobilephase: Hex:IPA=70:30, F: 1.0 mL/min, W: 230 nm, T: 30° C.) gavePreparation 223a (9.737 min, 32% yield) and Preparation 223b (11.171min, 29% yield), each as a yellow oil.

Example 223:3-({[(1S)-5-[(4-cyclopropylphenyl)(methyl)amino]-2,3-dihydro-1H-inden-1-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 78% yield from Preparation 223aaccording to the procedure for Example 217. ¹H NMR (400 MHz, DMSO-d₆): δ0.52-0.61 (2H, m), 0.86-0.91 (2H, m), 1.23 (1H, s), 1.81-1.87 (2H, m),2.22-2.25 (1H, m), 2.76-2.78 (1H, m), 2.86-2.90 (1H, m), 3.18 (3H, s),3.32-3.40 (1H, m), 3.58-3.62 (1H, m), 6.73 (1H, d, J=6.3 Hz), 6.82-6.88(3H, m), 6.97-6.99 (2H, m), 7.21 (1H, d, J=6.0 Hz), 7.56 (1H, d, J=3.6Hz), 7.84 (1H, d, J=3.9 Hz), 8.34 (1H, s).

[M+H] Calc'd for C₂₆H₂₇N₃O₂, 414; Found, 414.

Example 224:3-({[(1R)-5-[(4-cyclopropylphenyl)(methyl)amino]-2,3-dihydro-1H-inden-1-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 91% yield from Preparation 223baccording to the procedure for Example 217. ¹H NMR (400 MHz, DMSO-d₆): δ0.52-0.61 (2H, m), 0.86-0.91 (2H, m), 1.23 (1H, s), 1.81-1.87 (2H, m),2.22-2.25 (1H, m), 2.76-2.78 (1H, m), 2.86-2.90 (1H, m), 3.18 (3H, s),3.32-3.40 (1H, m), 3.58-3.62 (1H, m), 6.73 (1H, d, J=6.3 Hz), 6.82-6.88(3H, m), 6.97-6.99 (2H, m), 7.21 (1H, d, J=6.0 Hz), 7.56 (1H, d, J=3.6Hz), 7.84 (1H, d, J=3.9 Hz), 8.34 (1H, s). [M+H] Calc'd for C₂₆H₂₇N₃O₂,414; Found, 414.

Preparation 225a: 1,3-dimethyl 2-(4-bromo-2-nitrophenyl)propanedioate

To a solution of dimethyl malonate (7.8 mL, 68.2 mmol) in DME (100 mL)at 0° C. was added K₂CO₃ (12.6 g, 91.0 mmol). The reaction mixture wasstirred for 30 min, and then 4-bromo-1-fluoro-2-nitrobenzene (10.0 g,45.5 mmol) was added. The reaction mixture stirred at 40° C. overnight.The reaction was cooled, diluted with water (200 mL), and extracted withEtOAc (100 mL×3). The combined organic layers were washed with brine(100 mL), dried (Na₂SO₄) and concentrated. The residue was trituratedwith PE:EtOAc=8:1 (30 mL) to 13.0 g (86%) of the title compound as ayellow solid. [M+H] Calc'd for C₁₁H₁₀BrNO₆, 332, 334; Found, 332, 334.

Preparation 225b: 2-(4-bromo-2-nitrophenyl)propane-1,3-diol

To a solution of Preparation 225a (500 mg, 1.5 mmol) in dioxane (20 mL)was added BH₃-Me₂S (2.3 mL, 1.0 M in THF, 2.3 mmol) at rt. The reactionwas stirred at 70° C. overnight. The reaction was cooled, diluted withwater (20 mL), basified to pH 5 with sat. Na₂CO₃, and extracted withEtOAc (50 mL×3). The combined organic layers were washed with brine (100mL), dried (Na₂SO₄), and concentrated. The residue was purified bysilica gel chromatography (PE:EtOAc=3:2) to give 200 mg (48%) of thetitle compound as a yellow solid. [M+H] Calc'd for C₉H₁₀BrNO₄, 276, 278;Found, 276, 278.

Preparation 225c: 2-(2-amino-4-bromophenyl)propane-1,3-diol

To a suspension of Preparation 225b (100 mg, 0.36 mmol) and NH₄Cl (10mg, 0.18 mmol) in dioxane (20 mL) was added Fe (203 mg, 3.60 mmol) atrt. The reaction was stirred at 80° C. for 2 h. The reaction wasfiltered through Celite. The filtrate was diluted with EtOAc (50 mL),washed with water (50 mL) and brine (50 mL), dried (Na₂SO₄), andconcentrated. The residue was purified by silica gel chromatography(PE:EtOAc=1:1) to give 80 mg (90%) of the title compound as a yellowsolid. [M+H] Calc'd for C₉H₁₂BrNO₂, 246, 248; Found, 246, 248.

Preparation 225d: (6-bromo-2,3-dihydro-1-benzofuran-3-yl)methanol

To a solution of Preparation 225c (200 mg, 0.81 mmol) in water (4 mL)and conc. H₂SO₄ (1 mL) was added a solution of NaNO₂ (61 mg, 0.89 mmol)in water (2 mL) at 0° C. The reaction was stirred at rt for 1.5 h, andat 50° C. for 10 min. The reaction was diluted with EtOAc (20 mL),basified to pH 5 with sat. Na₂CO₃, and extracted with EtOAc (30 mL×3).The combined organic layers were washed with brine (50 mL), dried(Na₂SO₄), and concentrated. The residue was purified by silica gelchromatography (PE:EtOAc=3:2) to give 81 mg (44%) of the title compoundas a yellow oil. ¹H NMR (300 MHz, CDCl₃): δ 3.56-3.61 (1H, m), 3.78 (2H,dd, J=0.9, 5.7 Hz), 4.47-4.52 (1H, m), 4.66 (1H, t, J=9.0 Hz), 6.95-7.01(2H, m), 7.07 (1H, d, J=8.1 Hz).

Preparation 225e: (6-bromo-2,3-dihydro-1-benzofuran-3-yl)methylmethanesulfonate

To a solution of Preparation 225d (520 mg, 2.3 mmol) in pyridine (0.5mL) and DCM (20 mL) was added MsCl (0.2 mL, 2.7 mmol) at 0° C. Thereaction was stirred at rt overnight. The reaction was diluted withwater (30 mL), and extracted with DCM (30 mL×3). The combined organiclayers were washed with 0.1N HCl (10 mL×2) and brine (50 mL), dried(Na₂SO₄), and concentrated to give 650 mg (93%) of the crude titlecompound as a yellow solid.

Preparation 225f: 3-(azidomethyl)-6-bromo-2,3-dihydro-1-benzofuran

To a solution of Preparation 225e (200 mg, 0.65 mmol) in DMF (10 mL) wasadded NaN₃ (47 mg, 0.72 mmol) at rt. The reaction was stirred at 55° C.overnight. The solution was diluted with water (50 mL) and extractedwith EtOAc (30 mL×3). The combined organic layers were washed with brine(50 mL), dried (Na₂SO₄) and concentrated. The residue was purified bysilica gel chromatography (PE:EA=10:1) to give 107 mg (65%) of the titlecompound as a yellow oil. ¹H NMR (300 MHz, CDCl₃): δ 3.44-3.63 (3H, m),4.37-4.42 (1H, m), 4.65 (1H, t, J=9.0 Hz), 6.97-7.03 (2H, m), 7.08 (1H,d, J=7.8 Hz).

Preparation 225g: (6-bromo-2,3-dihydro-1-benzofuran-3-yl)methanamine

To a solution of Preparation 225f (70 mg, 0.28 mmol) in THF (10 mL) andwater (0.5 mL) was added PPh₃ (110 mg, 0.42 mmol) at rt, and thereaction was stirred overnight. The reaction was diluted with water (30mL), acidified to pH=3 with 1N HCl, and washed with EtOAc (30 mL×2). Theaqueous layer was basified to pH=9 with sat. Na₂CO₃ and extracted withEtOAc (30 mL×3). The combined organic layers were dried (Na₂SO₄) andconcentrated to give 50 mg (78%) of the title compound as a yellow oil.[M+H] Calc'd for C₉H₁₀BrNO, 228, 230; Found, 228, 230.

Preparation 225h: Methyl3-{[(6-bromo-2,3-dihydro-1-benzofuran-3-yl)methyl]amino}pyridine-4-carboxylate

The title compound was prepared in 63% yield from Preparation 225gaccording to the procedure for Preparation 217c. [M+H] Calc'd forC₁₆H₁₅BrN₂O₃, 363; Found, 363.

Preparation 225j: Methyl3-({[(3S)-6-[methyl(4-methylphenyl)amino]-2,3-dihydro-1-benzofuran-3-yl]methyl}amino)pyridine-4-carboxylate;and Preparation 225k: Methyl3-({[(3R)-6-[methyl(4-methylphenyl)amino]-2,3-dihydro-1-benzofuran-3-yl]methyl}amino)pyridine-4-carboxylate

The racemate of the title compounds was prepared in 60% yield fromPreparation 225h and N-methyl-p-toluidine according to the procedure forPreparation 217d and 217e. [M+H] Calc'd for C₂₄H₂₅N₃O₃, 404; Found, 404.

Separation by chiral prep-HPLC (Column: Chiralcel: IC 5 um 4.6*250 mm,Mobile phase: Hex:EtOH=50:50, F: 1.0 mL/min, W: 230 nm, T: 30° C.) gavePreparation 225j (7.814 min, 33% yield) and Preparation 225k (10.720min, 38% yield), each as a yellow oil.

Example 225:3-({[(3S)-6-[methyl(4-methylphenyl)amino]-2,3-dihydro-1-benzofuran-3-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 97% yield from Preparation 225jaccording to the procedure for Example 217. ¹H NMR (300 MHz, DMSO-d₆): δ2.24 (3H, s), 3.15 (3H, s), 3.47 (2H, d, J=6.9 Hz), 3.67-3.71 (1H, m),4.29-4.34 (1H, m), 4.57 (1H, t, J=8.7 Hz), 6.27-6.34 (2H, m), 6.92 (2H,d, J=8.1 Hz), 7.08-7.14 (3H, m), 7.54 (1H, d, J=5.4 Hz), 7.83 (1H, d,J=5.1 Hz), 8.33 (1H, s). [M+H] Calc'd for C₂₃H₂₃N₃O₃, 390; Found, 390.

Example 226:3-({[(3R)-6-[methyl(4-methylphenyl)amino]-2,3-dihydro-1-benzofuran-3-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 98% yield from Preparation 225kaccording to the procedure for Example 217. ¹H NMR (300 MHz, DMSO-d₆): δ2.24 (3H, s), 3.15 (3H, s), 3.47 (2H, d, J=6.9 Hz), 3.67-3.71 (1H, m),4.29-4.34 (1H, m), 4.57 (1H, t, J=8.7 Hz), 6.27-6.34 (2H, m), 6.92 (2H,d, J=8.1 Hz), 7.08-7.14 (3H, m), 7.54 (1H, d, J=5.4 Hz), 7.83 (1H, d,J=5.1 Hz), 8.33 (1H, s). [M+H] Calc'd for C₂₃H₂₃N₃O₃, 390; Found, 390.

Preparation 227a: Methyl3-({[(3S)-6-[(4-cyclopropylphenyl)(methyl)amino]-2,3-dihydro-1-benzofuran-3-yl]methyl}amino)pyridine-4-carboxylate;and Preparation 227b: Methyl3-({[(3R)-6-[(4-cyclopropylphenyl)(methyl)amino]-2,3-dihydro-1-benzofuran-3-yl]methyl}amino)pyridine-4-carboxylate

The racemate of the title compounds was prepared in 70% yield fromPreparation 225h and 4-cyclopropyl-N-methylaniline according to theprocedure for Preparation 217d and 217e. [M+H] Calc'd for C₂₄H₂₅N₃O₃,404; Found, 404. [M+H] Calc'd for C₂₆H₂₇N₃O₃, 430; Found, 430.

Separation by chiral prep-HPLC (Column: Chiralcel: IC 5 um 4.6*250 mm,Mobile phase: Hex:EtOH=50:50, F: 1.0 mL/min, W: 230 nm, T: 30° C.) gavePreparation 227a (8.246 min, 17% yield) and Preparation 227b (11.339min, 19% yield), each as a yellow oil.

Example 227:3-({[(3S)-6-[(4-cyclopropylphenyl)(methyl)amino]-2,3-dihydro-1-benzofuran-3-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 98% yield from Preparation 227aaccording to the procedure for Example 217. ¹H NMR (300 MHz, DMSO-d₆): δ0.57-0.62 (2H, m), 0.85-0.91 (2H, m), 1.82-1.87 (1H, m), 3.14 (3H, s),3.48 (2H, d, J=6.3 Hz), 3.67-3.71 (1H, m), 4.29-4.34 (1H, m), 4.57 (1H,t, J=9.0 Hz), 6.26-6.33 (2H, m), 6.91 (2H, d, J=8.7 Hz), 6.98 (2H, d,J=8.7 Hz), 7.12 (1H, d, J=7.8 Hz), 7.54 (1H, d, J=4.8 Hz), 7.83 (1H, d,J=4.8 Hz), 8.35 (1H, s).

[M+H] Calc'd for C₂₅H₂₅N₃O₃, 416; Found, 416.

Example 228:3-({[(3R)-6-[(4-cyclopropylphenyl)(methyl)amino]-2,3-dihydro-1-benzofuran-3-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 94% yield from Preparation 227baccording to the procedure for Example 217. ¹H NMR (300 MHz, DMSO-d₆): δ0.57-0.62 (2H, m), 0.85-0.91 (2H, m), 1.82-1.87 (1H, m), 3.14 (3H, s),3.48 (2H, d, J=6.3 Hz), 3.67-3.71 (1H, m), 4.29-4.34 (1H, m), 4.57 (1H,t, J=9.0 Hz), 6.26-6.33 (2H, m), 6.91 (2H, d, J=8.7 Hz), 6.98 (2H, d,J=8.7 Hz), 7.12 (1H, d, J=7.8 Hz), 7.54 (1H, d, J=4.8 Hz), 7.83 (1H, d,J=4.8 Hz), 8.35 (1H, s). [M+H] Calc'd for C₂₅H₂₅N₃O₃, 416; Found, 416.

Preparation 229a: 4-bromo-2-(chloromethyl)-1-iodobenzene

To a solution of (5-bromo-2-iodophenyl)methanol (1.4 g, 4.5 mmol) in DCM(20 mL) was added SOCl₂ (3.2 g, 26.9 mmol) at 0° C., and the reactionwas stirred at rt overnight. The solution was concentrated, and theresidue was purified silica gel chromatography (PE) to give 1.2 g (81%)of the title compound as a brown solid.

Preparation 229b:[(5-bromo-1,3-dihydro-2-benzofuran-1-yl)methoxy](tert-butyl)dimethylsilane

To a solution of Preparation 229a (1.0 g, 3.0 mmol) in THF (25 mL) wasadded i-PrMgBr (1.6 mL, 2.0 M in THF, 3.2 mmol) at −10° C., and themixture was stirred for 2 min. (tert-Butyl-dimethylsiloxy)acetaldehyde(578 g, 3.3 mmol) was added at −10° C. The reaction mixture was stirredat rt for 1 h, and then was heated at reflux overnight. The reaction wascooled, diluted with water (30 mL), and extracted with EtOAc (50 mL×3).The combined organic layers were washed with brine (100 mL), dried(Na₂SO₄), and concentrated. The residue was purified by silica gelchromatography (PE) to give 680 mg (66%) of the title compound as ayellow oil. ¹H NMR (300 MHz, CDCl₃): δ 0.02 (3H, s), 0.04 (3H, s), 0.86(9H, s), 3.72-3.78 (1H, m), 3.82-3.87 (1H, m), 5.02-5.18 (3H, m), 7.15(1H, d, J=8.1 Hz), 7.35-7.39 (2H, m). [M+H] Calc'd for C₁₅H₂₃BrO₂Si,343, 345; Found, 343, 345.

Preparation 229c: (5-bromo-1,3-dihydro-2-benzofuran-1-yl)methanol

To a solution of Preparation 229b (5.0 g, 14.6 mmol) in THF (100 mL) wasadded TBAF (27.4 mL, 1.0 M in THF, 24.7 mmol) at rt, and the reactionwas stirred for 30 min. The reaction was diluted with water (100 mL),and extracted with EtOAc (50 mL×3). The combined organic layers werewashed with brine (50 mL), dried (Na₂SO₄), and concentrated to give 3.0g (90%) of the title compound as a white solid. [M+H] Calc'd forC₉H₉BrO₂, 229, 231; Found, 229, 231.

Preparation 229d: (5-bromo-1,3-dihydro-2-benzofuran-1-yl)methylmethanesulfonate

To a solution of Preparation 229c (5.0 g, 13.2 mmol) in pyridine (3 mL)and DCM (100 mL) was added MsCl (1.2 mL, 15.8 mmol) at 0° C., and thereaction was stirred at rt overnight. The solution was diluted withwater (100 mL) and extracted with DCM (50 mL×3). The combined organiclayers were washed with 0.1 N HCl (20 mL×2) and brine (50 mL), dried(Na₂SO₄), and concentrated to give 4.0 g (100%) of the title compound asa colorless oil.

Preparation 229e: 1-(azidomethyl)-5-bromo-1,3-dihydro-2-benzofuran

To a solution of Preparation 229d (4.0 g, 13.1 mmol) in DMF (50 mL) wasadded NaN₃ (898 mg, 13.8 mmol) at rt, and the reaction was stirred at60° C. overnight. The reaction was diluted with water (100 mL) andextracted with EtOAc (80 mL×3). The combined organic layers were washedwith brine (100 mL), dried (Na₂SO₄), and concentrated. The residue waspurified by silica gel chromatography (PE:EA=10:1) to give 1.9 g (57%)of the title compound as a yellow oil.

Preparation 229f: (5-bromo-1,3-dihydro-2-benzofuran-1-yl)methanamine

To a solution of Preparation 229e (1.9 g, 7.5 mmol) in THF (50 mL) andwater (8 mL) was added PPh₃ (3.0 g, 11.3 mmol) at rt, and the reactionwas stirred at 60° C. overnight. The reaction was diluted with water (50mL), acidified to pH=3 with 1N HCl, and washed with EtOAc (50 mL×2). Theaqueous layer was basified to pH=9 with sat. Na₂CO₃ and extracted withEtOAc (50 mL×3). The combined organic layers were dried (Na₂SO₄)concentrated to give 1.0 g (59%) of the title compound as a yellow oil.[M+H] Calc'd for C₉H₁₀BrNO, 228, 230; Found, 228, 230.

Preparation 229g: Methyl3-{[(5-bromo-1,3-dihydro-2-benzofuran-1-yl)methyl]amino}pyridine-4-carboxylate

The title compound was prepared in 53% yield from Preparation 229faccording to the procedure for Preparation 217c. [M+H] Calc'd forC₁₆H₁₅BrN₂O₃, 363, 365; Found, 363, 365.

Preparation 229h: Methyl3-({[(1S)-5-[methyl(4-methylphenyl)amino]-1,3-dihydro-2-benzofuran-1-yl]methyl}amino)pyridine-4-carboxylate;and Preparation 229j: methyl3-({[(1S)-5-[methyl(4-methylphenyl)amino]-1,3-dihydro-2-benzofuran-1-yl]methyl}amino)pyridine-4-carboxylate

The racemate of the title compounds was prepared in 75% yield fromPreparation 229g and N-methyl-p-toluidine according to the procedure forPreparation 217d and 217e. [M+H] Calc'd for C₂₄H₂₅N₃O₃, 404; Found, 404.

Separation by chiral prep-HPLC (Column: Chiralcel: IE 5 um 4.6*250 mm,Mobile phase: Hex:EtOH=50:50, F: 1.0 mL/min, W: 230 nm, T: 30° C.) gavePreparation 229h (9.673 min, 16% yield) and Preparation 229j (11.741min, 18% yield), each as a yellow oil.

Example 229:3-({[(1S)-5-[methyl(4-methylphenyl)amino]-1,3-dihydro-2-benzofuran-1-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 90% yield from Preparation 229haccording to the procedure for Example 217. ¹H NMR (300 MHz, DMSO-d₆): δ2.26 (3H, s), 3.20 (3H, s), 3.48-3.54 (1H, m), 3.74-3.78 (1H, m),4.90-4.99 (2H, m), 5.33-5.35 (1H, m), 6.78-6.80 (2H, m), 6.94 (2H, d,J=8.1 Hz), 7.12 (2H, d, J=8.1 Hz), 7.24 (1H, d, J=8.4 Hz), 7.54 (1H, d,J=5.1 Hz), 7.82 (1H, d, J=5.1 Hz), 8.38 (1H, s). [M+H] Calc'd forC₂₃H₂₃N₃O₃, 390; Found, 390.

Example 230:3-({[(1R)-5-[methyl(4-methylphenyl)amino]-1,3-dihydro-2-benzofuran-1-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 93% yield from Preparation 229jaccording to the procedure for Example 217. ¹H NMR (300 MHz, DMSO-d₆): δ2.26 (3H, s), 3.20 (3H, s), 3.48-3.54 (1H, m), 3.74-3.78 (1H, m),4.90-4.99 (2H, m), 5.33-5.35 (1H, m), 6.78-6.80 (2H, m), 6.94 (2H, d,J=8.1 Hz), 7.12 (2H, d, J=8.1 Hz), 7.24 (1H, d, J=8.4 Hz), 7.54 (1H, d,J=5.1 Hz), 7.82 (1H, d, J=5.1 Hz), 8.38 (1H, s). [M+H] Calc'd forC₂₃H₂₃N₃O₃, 390; Found, 390.

Preparation 231a: 6-bromo-1H-indene-3-carboxamide

To a solution of 5-bromo-1-indanone (50 g, 0.23 mol) in toluene (2000mL) was added ZnI₂ (1.5 g), and the mixture was stirred at 40° C. untildissolved. TMSCN (76 mL, 0.57 mol) was added, and the reaction wasstirred at reflux for 6 h. The solution was concentrated, and theresidue was dissolved in 300 mL HOAc. While keeping the temperatureunder 25° C., concentrated H₂SO₄ (100 mL) was added, followed by water(30 mL), and then the reaction mixture was heated at 130° C. for 2 h.The solution was cooled to rt, diluted with water, and the solid wascollected by filtration. The filter cake was triturated in THF andcollected by filtration to give 25 g (44%) of the title compound asyellow solid. [M+H] Calc'd for C₁₀H₈BrNO, 238, 240; Found, 238, 240.

Preparation 231b: (1R)-5-bromo-2,3-dihydro-1H-indene-1-carboxamide

To a solution of Preparation 231a (5.0 g, 21 mmol) in MeOH/THF (200 mL,1:1) was added Ru(OAc)₂[s-binap] (250 mg). The mixture was stirredovernight at 60° C. under 5.0 M Pa of hydrogen. The mixture was filteredand concentrated to give 5.3 g (100%) of the crude title compound as abrown solid (ee>95%). [M+H] Calc'd for C₁₀H₁₀BrNO, 240, 242; Found, 240,242. Analytical Column: Chiralcel: AS-H, Mobile phase: Hex:EtOH=60:40.

Preparation 231c: [(1R)-5-bromo-2,3-dihydro-1H-inden-1-yl]methanamine

To a solution of Preparation 231b (5.3 g, 22 mmol) in THF (50 mL) wasadded BH₃-THF (110 mL, 110 mmol, 1.0 M). The resulting mixture wasstirred at rt overnight. The mixture was poured into water and extractedwith EtOAc. The combined organic layers were washed with brine, dried(Na₂SO₄), and concentrated to give 4.27 g (85%) of the title compound asa brown oil. [M+H] Calc'd for C₁₀H₁₂BrN, 226, 228; Found, 226, 228.

Preparation 231d: Methyl3-({[(1R)-5-bromo-2,3-dihydro-1H-inden-1-yl]methyl}amino)pyridine-4-carboxylate

To a solution of Preparation 231c (4.27 g, 18.9 mmol) in toluene (100mL) was added methyl 3-bromoisonicotinate (4.9 g, 23 mmol), Cs₂CO₃ (8.6g, 26 mmol), Xantphos (655 mg, 1.13 mmol) and Pd₂(dba)₃ (348 mg, 0.378mmol). The mixture was stirred overnight at 120° C. under nitrogen.After filtration and concentration, the residue was purified by silicagel chromatography (PE:EtOAc=2:1) to give 1.8 g (26%) of the titlecompound as a brown oil. [M+H] Calc'd for C₁₇H₁₇BrN₂O₂, 361, 363; Found,361, 363.

Preparation 231e: Methyl3-({[(1R)-5-[methyl(3-methylphenyl)amino]-2,3-dihydro-1H-inden-1-yl]methyl}amino)pyridine-4-carboxylate

To a solution of Preparation 231d (200 mg, 0.554 mmol) in toluene (15mL) was added compound N-methyl-m-toluidine (80 mg, 0.66 mmol), Cs₂CO₃(253 mg, 0.776 mmol), Xantphos (48 mg, 0.083 mmol) and Pd₂(dba)₃ (26 mg,0.028 mmol). The mixture was stirred overnight at 120° C. undernitrogen. After filtration and concentration, the residue was purifiedby prep-HPLC to give 62 mg (28%) of the title compound as a yellow oil.[M+H] Calc'd for C₂₅H₂₇N₃O₃, 402; Found, 402.

Example 231:3-({[(1R)-5-[methyl(3-methylphenyl)amino]-2,3-dihydro-1H-inden-1-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 75% yield from Preparation 231daccording to the procedure for Example 217. ¹H NMR (300 MHz, DMSO-d₆): δ1.79-1.85 (1H, m), 2.21-2.27 (4H, m), 2.72-2.96 (2H, m), 3.15 (3H, s),3.37-3.41 (2H, m), 3.58-3.62 (1H, m), 6.65-6.72 (3H, m), 6.80 (1H, d,J=8.1 Hz), 6.89 (1H, s), 7.06-7.11 (1H, m), 7.24 (1H, d, J=8.1 Hz), 7.54(1H, d, J=4.8 Hz), 7.82 (1H, d, J=5.4 Hz), 8.33 (1H, s). [M+H] Calc'dfor C₂₄H₂₅N₃O₂, 388; Found, 388.

Preparation 232a: Methyl3-({[(1R)-5-[(4-ethylphenyl)(methyl)amino]-2,3-dihydro-1H-inden-1-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 26% yield from Preparation 231d and4-ethyl-N-methylaniline according to the procedure for Preparation 231e.[M+H] Calc'd for C₂₆H₂₉N₃O₂, 416; Found, 416.

Example 232:3-({[(1R)-5-[(4-ethylphenyl)(methyl)amino]-2,3-dihydro-1H-inden-1-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 77% yield from Preparation 232aaccording to the procedure for Example 217. ¹H NMR (300 MHz, DMSO-d₆): δ1.14 (3H, t, J=7.5 Hz), 1.77-1.84 (1H, m), 2.16-2.25 (1H, m), 2.53 (2H,m), 2.72-2.79 (1H, m), 2.84-2.92 (1H, m), 3.17 (3H, s), 3.24-3.30 (2H,m), 3.55-3.60 (1H, m), 6.73 (1H, dd, J=1.5, 8.4 Hz), 6.82-6.88 (3H, m),7.08 (2H, d, J=8.4 Hz), 7.20 (1H, d, J=7.8 Hz), 7.55 (1H, d, J=5.1 Hz),7.82 (1H, d, J=5.1 Hz), 8.32 (1H, s). [M+H] Calc'd for C₂₅H₂₇N₃O₂, 402;Found, 402.

Preparation 233a: Methyl3-({[(1R)-5-{methyl[4-(pyrrolidin-1-yl)phenyl]amino}-2,3-dihydro-1H-inden-1-yl]methyl}amino)pyridine-4-carboxylate

The title compound was prepared in 28% yield from Preparation 231d andN-methyl-4-(pyrrolidin-1-yl)aniline according to the procedure forPreparation 231e. [M+H] Calc'd for C₂₈H₃₂N₄O₂, 457; Found, 457.

Example 233:3-({[(1R)-5-{methyl[4-(pyrrolidin-1-yl)phenyl]amino}-2,3-dihydro-1H-inden-1-yl]methyl}amino)pyridine-4-carboxylicAcid

The title compound was prepared in 47% yield from Preparation 233aaccording to the procedure for Example 217. ¹H NMR (300 MHz, DMSO-d₆):1.77 (1H, m), 1.79 (4H, m), 2.20-2.22 (1H, m), 2.70-2.73 (1H, m),2.82-2.84 (1H, m), 3.13 (3H, s), 3.22 (4H, m), 3.32 (2H, m), 3.47-3.49(1H, m), 6.48 (4H, m), 6.95-6.97 (2H, d, J=6.0 Hz), 7.09-7.12 (1H, m),7.55-7.57 (1H, d, J=6.9 Hz), 7.79 (1H, d, J=5.1 Hz), 8.24 (1H, s). [M+H]Calc'd for C₂₇H₃₀N₄O₂, 442; Found, 443.

II. Biological Evaluation Example 1a: In Vitro Enzyme Inhibition Assayfor JMJD2C Activity

This assay determines the ability of a test compound to inhibit JMJD2Cdemethylase activity. Baculovirus expressed JMJD2C (GenBank Accession#BC143571, AA 2-372) was purchased from BPS Bioscience (Cat#50105).

JMJD2C Assay

The ability of test compounds to inhibit the activity of JMJD2C wasdetermined in 384-well plate format under the following reactionconditions: 0.3 nM JMJD2C, 300 nM H3K9me3-biotin labeled peptide(Anaspec cat #64360), 2 μM alpha-ketoglutaric acid in assay buffer of 50mM HEPES, pH7.3, 0.005% Brij35, 0.5 mM TCEP, 0.2 mg/ml BSA, 50 μM sodiumL-ascorbate, and 2 μM ammonium iron(II) sulfate. Reaction product wasdetermined quantitatively by TR-FRET after the addition of detectionreagent Phycolink Streptavidin-allophycocyanin (Prozyme) andEuropium-anti-di-methylated histone H3 lysine 9 (H3K9me2) antibody(PerkinElmer) in the presence of 5 mM EDTA in LANCE detection buffer(PerkinElmer) at a final concentration of 50 nM and 1 nM, respectively.

The assay reaction was initiated by the following: 2 μl of the mixtureof 900 nM H3K9me3-biotin labeled peptide and 6 μM alpha-ketoglutaricacid with 2 μl of 11-point serial diluted inhibitor in 3% DMSO wereadded to each well of the plate, followed by the addition of 2 μl of 0.9nM JMJD2C to initiate the reaction. The reaction mixture was incubatedat room temperature for 30 minutes, and terminated by the addition of 6μl of 5 mM EDTA in LANCE detection buffer containing 100 nM PhycolinkStreptavidin-allophycocyanin and 2 nM Europium-anti-H3K9me2 antibody.Plates were read by EnVisionMultilabel Reader in TR-FRET mode(excitation at 320 nm, emission at 615 nm and 665 nm) after 1 hourincubation at room temperature. A ratio was calculated (665/615) foreach well and fitted to determine inhibition constant (IC₅₀).

Example 1b: In Vitro Enzyme Inhibition Assay for JMJD3 Activity

This assay determines the ability of a test compound to inhibit JMJD3demethylase activity. Baculovirus expressed JMJD3 (GenBank Accession#NM-001080424, AA1043-end) was purchased from BPS Bioscience(Cat#50115).

JMJD3 Assay

The enzymatic assay of JMJD3 activity is based upon TimeResolved-Fluorescence Resonance Energy Transfer (TR-FRET) detection. Theability of test compounds to inhibit the activity of JMJD3 wasdetermined in 384-well plate format under the following reactionconditions: 5 nM JMJD3, 250 nM H3K27me3-biotin labeled peptide (Anaspeccat #64367), 0.4 to 2 μM alpha-ketoglutaric acid in assay buffer of 50mM HEPES, pH7.3, 0.005% Brij35, 0.5 mM TCEP, 0.2 mg/ml BSA, 50 μM sodiumL-ascorbate, and 5 μM ammonium iron(II) sulfate. Reaction product wasdetermined quantitatively by TR-FRET after the addition of detectionreagent Phycolink Streptavidin-allophycocyanin (Prozyme) andEuropium-anti-di-methylated histone H3 lysine 27 (H3K27me2) antibody(PerkinElmer) in the presence of 5 mM EDTA in LANCE detection buffer(PerkinElmer) at a final concentration of 50 nM and 1 nM, respectively.

The assay reaction was initiated by the following: 2 μl of the mixtureof 750 nM H3K27me3-biotin labeled peptide and 1.2 to 6 μMalpha-ketoglutaric acid with 2 μL of 11-point serial diluted inhibitorin 3% DMSO were added to each well of plate, followed by the addition of2 μl of 15 nM JMJD3 to initiate the reaction. The reaction mixture wasincubated at room temperature for 30 minutes, and terminated by theaddition of 6 μL of 5 mM EDTA in LANCE detection buffer containing 100nM Phycolink Streptavidin-allophycocyanin and 2 nMEuropium-anti-H3K27me2 antibody. Plates were read by EnVisionMultilabelReader in TR-FRET mode (excitation at 320 nm, emission at 615 nm and 665nm) after 1 hour incubation at room temperature. A ratio from thereadout of 665/615 was calculated for each well and fitted to determineinhibition constant (IC₅₀).

The ability of the compounds disclosed herein to inhibit demethylaseactivity was quantified and the respective IC₅₀ value was determined.Table 3 provides the IC₅₀ values of various compounds disclosed herein.

TABLE 3 Chemical Synthesis JMJD2C JMJD3 Example Name IC₅₀ (nM) IC₅₀ (nM)1 3-({[(1S)-6-[methyl(phenyl)amino]-1,2,3,4-tetrahydronaphthalen-1- C Cyl]methyl}amino)pyridine-4-carboxylic acid 23-({[(1S)-6-[methyl(phenyl)amino]-1,2,3,4-tetrahydronaphthalen-1- B Cyl]methyl}amino)pyridine-4-carboxylic acid 33-({[6-(2-oxopyrrolidin-1-yl)-1,2,3,4-tetrahydronaphthalen-1- Byl]methyl}amino)pyridine-4-carboxylic acid 43-({[6-(1,2,3,4-tetrahydroquinolin-1-yl)-1,2,3,4- Ctetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 53-({[6-(2,3-dihydro-1H-indol-1-yl)-1,2,3,4-tetrahydronaphthalen-1- Cyl]methyl}amino)pyridine-4-carboxylic acid 63-({[(1R)-6-[(2-fluorophenyl)(methyl)amino]-1,2,3,4- Btetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 73-({[(1R)-6-[(3-fluorophenyl)(methyl)amino]-1,2,3,4- Btetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 83-({[(1R)-6-[(4-fluorophenyl)(methyl)amino]-1,2,3,4- Btetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 93-({[(1R)-6-[(4-chlorophenyl)(methyl)amino]-1,2,3,4- Ctetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 103-({[(1R)-6-[ethyl(phenyl)amino]-1,2,3,4-tetrahydronaphthalen-1- Byl]methyl}amino)pyridine-4-carboxylic acid 113-({[(1R)-6-[methyl(pyridin-2-yl)amino]-1,2,3,4- B Ctetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 123-({[(1R)-6-[methyl(pyridin-3-yl)amino]-1,2,3,4- Atetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 133-({[(1R)-6-[(6-methoxypyridin-3-yl)(methyl)amino]-1,2,3,4- Btetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 143-{[(7-bromo-3,4-dihydro-2H-1-benzopyran-4- Byl)methyl]amino}pyridine-4-carboxylic acid 153-({[7-(phenylamino)-3,4-dihydro-2H-1-benzopyran-4- Byl]methyl}amino)pyridine-4-carboxylic acid 163-({[7-(1,2,3,4-tetrahydroquinolin-1-yl)-3,4-dihydro-2H-1- B Cbenzopyran-4-yl]methyl}amino)pyridine-4-carboxylic acid 173-({[7-(2,3-dihydro-1H-indol-1-yl)-3,4-dihydro-2H-1-benzopyran- B C4-yl]methyl}amino)pyridine-4-carboxylic acid 183-({[(4R)-7-[methyl(phenyl)amino]-3,4-dihydro-2H-1-benzopyran- B B4-yl]methyl}amino)pyridine-4-carboxylic acid 193-({[(4R)-7-[(2-fluorophenyl)(methyl)amino]-3,4-dihydro-2H-1- Bbenzopyran-4-yl]methyl}amino)pyridine-4-carboxylic acid 203-({[(4R)-7-[(3-fluorophenyl)(methyl)amino]-3,4-dihydro-2H-1- B Cbenzopyran-4-yl]methyl}amino)pyridine-4-carboxylic acid 213-({[(4R)-7-[(4-fluorophenyl)(methyl)amino]-3,4-dihydro-2H-1- B Cbenzopyran-4-yl]methyl}amino)pyridine-4-carboxylic acid 223-({[(4R)-7-[methyl(4-methylphenyl)amino]-3,4-dihydro-2H-1- B Cbenzopyran-4-yl]methyl}amino)pyridine-4-carboxylic acid 233-({[(4R)-7-[(4-chlorophenyl)(methyl)amino]-3,4-dihydro-2H-1- B Cbenzopyran-4-yl]methyl}amino)pyridine-4-carboxylic acid 243-({[(4R)-7-[ethyl(phenyl)amino]-3,4-dihydro-2H-1-benzopyran-4- B Cyl]methyl}amino)pyridine-4-carboxylic acid 253-{[(2-phenyl-5,6,7,8-tetrahydroquinolin-5- B Byl)methyl]amino}pyridine-4-carboxylic acid 263-[({2-[methyl(phenyl)amino]-5,6,7,8-tetrahydroquinolin-5- B Cyl}methyl)amino]pyridine-4-carboxylic acid 273-[({7-[4-(trifluoromethyl)phenyl]-3,4-dihydro-2H-1-benzopyran- C4-yl}methyl)amino]pyridine-4-carboxylic acid 283-({[7-(furan-3-yl)-3,4-dihydro-2H-1-benzopyran-4- B Ayl]methyl}amino)pyridine-4-carboxylic acid 293-({[(4S)-7-(3-methylphenyl)-3,4-dihydro-2H-1-benzopyran-4- C Byl]methyl}amino)pyridine-4-carboxylic acid 303-({[(4R)-7-(3-methylphenyl)-3,4-dihydro-2H-1-benzopyran-4- Byl]methyl}amino)pyridine-4-carboxylic acid 313-({[(4S)-7-(4-methylphenyl)-3,4-dihydro-2H-1-benzopyran-4- C Byl]methyl}amino)pyridine-4-carboxylic acid 323-({[(4R)-7-(4-methylphenyl)-3,4-dihydro-2H-1-benzopyran-4- Byl]methyl}amino)pyridine-4-carboxylic acid 333-({[(4S)-7-(thiophen-3-yl)-3,4-dihydro-2H-1-benzopyran-4- C Ayl]methyl}amino)pyridine-4-carboxylic acid 343-({[(4R)-7-(thiophen-3-yl)-3,4-dihydro-2H-1-benzopyran-4- B Cyl]methyl}amino)pyridine-4-carboxylic acid 353-({[(4R)-7-cyclohexyl-3,4-dihydro-2H-1-benzopyran-4- Byl]methyl}amino)pyridine-4-carboxylic acid 363-({[(4S)-7-(2-methylthiophen-3-yl)-3,4-dihydro-2H-1- C Bbenzopyran-4-yl]methyl}amino)pyridine-4-carboxylic acid 373-({[(4R)-7-(2-methylthiophen-3-yl)-3,4-dihydro-2H-1- C Cbenzopyran-4-yl]methyl}amino)pyridine-4-carboxylic acid 383-({[7-(3-methylbut-1-yn-1-yl)-3,4-dihydro-2H-1-benzopyran-4- Byl]methyl}amino)pyridine-4-carboxylic acid 393-({[(4S)-7-(2-chlorophenyl)-3,4-dihydro-2H-1-benzopyran-4- C Byl]methyl}amino)pyridine-4-carboxylic acid 403-({[(4R)-7-(2-chlorophenyl)-3,4-dihydro-2H-1-benzopyran-4- B Cyl]methyl}amino)pyridine-4-carboxylic acid 413-({[(4S)-7-(3-fluoro-2-methylphenyl)-3,4-dihydro-2H-1- Cbenzopyran-4-yl]methyl}amino)pyridine-4-carboxylic acid 423-({[(4R)-7-(3-fluoro-2-methylphenyl)-3,4-dihydro-2H-1- Bbenzopyran-4-yl]methyl}amino)pyridine-4-carboxylic acid 433-({[(4R)-7-(5-fluoro-2-methylphenyl)-3,4-dihydro-2H-1- Bbenzopyran-4-yl]methyl}amino)pyridine-4-carboxylic acid 443-({[(4R)-7-(2-chloro-3-fluorophenyl)-3,4-dihydro-2H-1- Bbenzopyran-4-yl]methyl}amino)pyridine-4-carboxylic acid 453-({[(4R)-7-(2-chloro-5-fluorophenyl)-3,4-dihydro-2H-1- Bbenzopyran-4-yl]methyl}amino)pyridine-4-carboxylic acid 463-({[(4R)-7-[2-(trifluoromethyl)phenyl]-3,4-dihydro-2H-1- Bbenzopyran-4-yl]methyl}amino)pyridine-4-carboxylic acid 473-({[(4S)-7-phenoxy-3,4-dihydro-2H-1-benzopyran-4- Cyl]methyl}amino)pyridine-4-carboxylic acid 483-({[(4R)-7-phenoxy-3,4-dihydro-2H-1-benzopyran-4- Byl]methyl}amino)pyridine-4-carboxylic acid 493-({[7-(thiophen-2-ylsulfanyl)-3,4-dihydro-2H-1-benzopyran-4- Byl]methyl}amino)pyridine-4-carboxylic acid 503-({[(4S)-7-[(2-methylphenyl)sulfanyl]-3,4-dihydro-2H-1- Cbenzopyran-4-yl]methyl}amino)pyridine-4-carboxylic acid 513-({[(4R)-7-[(2-methylphenyl)sulfanyl]-3,4-dihydro-2H-1- Bbenzopyran-4-yl]methyl}amino)pyridine-4-carboxylic acid 523-({[(4S)-7-[(3-fluorophenyl)sulfanyl]-3,4-dihydro-2H-1- C Bbenzopyran-4-yl]methyl}amino)pyridine-4-carboxylic acid 533-({[(4R)-7-[(3-fluorophenyl)sulfanyl]-3,4-dihydro-2H-1- Bbenzopyran-4-yl]methyl}amino)pyridine-4-carboxylic acid 543-({[(4S)-7-[(4-fluorophenyl)sulfanyl]-3,4-dihydro-2H-1- C Bbenzopyran-4-yl]methyl}amino)pyridine-4-carboxylic acid 553-({[(4R)-7-[(4-fluorophenyl)sulfanyl]-3,4-dihydro-2H-1- B Cbenzopyran-4-yl]methyl}amino)pyridine-4-carboxylic acid 563-[({6-[(6-methylpyridin-2-yl)oxy]-1,2,3,4-tetrahydronaphthalen-1- Byl}methyl)amino]pyridine-4-carboxylic acid 573-({[(1S)-6-(2-methylphenoxy)-1,2,3,4-tetrahydronaphthalen-1- Cyl]methyl}amino)pyridine-4-carboxylic acid 583-({[(1R)-6-(2-methylphenoxy)-1,2,3,4-tetrahydronaphthalen-1- Byl]methyl}amino)pyridine-4-carboxylic acid 593-{[(6-propoxy-1,2,3,4-tetrahydronaphthalen-1- Byl)methyl]amino}pyridine-4-carboxylic acid 603-({[(1S)-6-(difluoromethoxy)-1,2,3,4-tetrahydronaphthalen-1- Cyl]methyl}amino)pyridine-4-carboxylic acid 613-({[(1R)-6-(difluoromethoxy)-1,2,3,4-tetrahydronaphthalen-1- Byl]methyl}amino)pyridine-4-carboxylic acid 623-[({6-[2-(trifluoromethyl)phenoxy]-1,2,3,4-tetrahydronaphthalen- C1-yl}methyl)amino]pyridine-4-carboxylic acid 633-({[6-(oxan-4-ylmethoxy)-1,2,3,4-tetrahydronaphthalen-1- Byl]methyl}amino)pyridine-4-carboxylic acid 643-({[(1R)-6-(4-fluoro-2-methylphenoxy)-1,2,3,4- Btetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 653-({[(1R)-6-(2,4-difluorophenoxy)-1,2,3,4-tetrahydronaphthalen-1- Byl]methyl}amino)pyridine-4-carboxylic acid 663-({[(1R)-6-(2-fluoro-4-methylphenoxy)-1,2,3,4- B Ctetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 673-({[(1R)-6-(2-chlorophenoxy)-1,2,3,4-tetrahydronaphthalen-1- Byl]methyl}amino)pyridine-4-carboxylic acid 683-({[(1S)-6-[(3-methylphenyl)sulfanyl]-1,2,3,4- Ctetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 693-({[(1R)-6-[(3-methylphenyl)sulfanyl]-1,2,3,4- Ctetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 703-({[(1S)-6-[(2-methylphenyl)sulfanyl]-1,2,3,4- Ctetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 713-({[(1R)-6-[(2-methylphenyl)sulfanyl]-1,2,3,4- Ctetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 723-({[(1S)-6-[(2-fluorophenyl)sulfanyl]-1,2,3,4- Ctetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 733-({[(1R)-6-[(2-fluorophenyl)sulfanyl]-1,2,3,4- Btetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 743-({[(1S)-6-[(3-fluorophenyl)sulfanyl]-1,2,3,4- Ctetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 753-({[(1R)-6-[(3-fluorophenyl)sulfanyl]-1,2,3,4- Btetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 763-({[(1S)-6-[(4-fluorophenyl)sulfanyl]-1,2,3,4- Ctetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 773-({[(1R)-6-[(4-fluorophenyl)sulfanyl]-1,2,3,4- Btetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 783-({[(1S)-6-[(4-methylphenyl)sulfanyl]-1,2,3,4- Ctetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 793-({[(1R)-6-[(4-methylphenyl)sulfanyl]-1,2,3,4- Ctetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 803-({[6-(pyridin-2-ylsulfanyl)-1,2,3,4-tetrahydronaphthalen-1- Byl]methyl}amino)pyridine-4-carboxylic acid 813-({[(1S)-6-(benzenesulfonyl)-1,2,3,4-tetrahydronaphthalen-1- Byl]methyl}amino)pyridine-4-carboxylic acid 823-({[(1R)-6-(benzenesulfonyl)-1,2,3,4-tetrahydronaphthalen-1- Byl]methyl}amino)pyridine-4-carboxylic acid 833-({[(1S)-6-(4-methylbenzenesulfonyl)-1,2,3,4- Btetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 843-({[(1R)-6-(4-methylbenzenesulfonyl)-1,2,3,4- Btetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 853-({[(1S)-6-(3-methylbenzenesulfonyl)-1,2,3,4- Ctetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 863-({[(1R)-6-(3-methylbenzenesulfonyl)-1,2,3,4- Btetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 873-({[6-(3-fluorobenzenesulfonyl)-1,2,3,4-tetrahydronaphthalen-1- Byl]methyl}amino)pyridine-4-carboxylic acid 883-({[6-(oxan-4-yl)-1,2,3,4-tetrahydronaphthalen-1- Byl]methyl}amino)pyridine-4-carboxylic acid 893-({[6-(2-methylpyridin-4-yl)-1,2,3,4-tetrahydronaphthalen-1- Byl]methyl}amino)pyridine-4-carboxylic acid 903-({[(1S)-6-ethyl-1,2,3,4-tetrahydronaphthalen-1- Byl]methyl}amino)pyridine-4-carboxylic acid 913-({[(1R)-6-ethyl-1,2,3,4-tetrahydronaphthalen-1- Byl]methyl}amino)pyridine-4-carboxylic acid 923-({2H,3H,6H,7H,8H,9H-naphtho[1,2-b]furan-6- Bylmethyl}amino)pyridine-4-carboxylic acid 933-{[(6,7-dimethyl-3,4-dihydro-2H-1-benzopyran-4- Byl)methyl]amino}pyridine-4-carboxylic acid 943-{[(6-methoxy-7-methyl-1,2,3,4-tetrahydronaphthalen-1- Byl)methyl]amino}pyridine-4-carboxylic acid 953-{[(6,8-dimethoxy-1,2,3,4-tetrahydronaphthalen-1- Byl)methyl]amino}pyridine-4-carboxylic acid 963-({[(1S)-7-fluoro-6-methoxy-1,2,3,4-tetrahydronaphthalen-1- Byl]methyl}amino)pyridine-4-carboxylic acid 973-({[(1R)-7-fluoro-6-methoxy-1,2,3,4-tetrahydronaphthalen-1- Byl]methyl}amino)pyridine-4-carboxylic acid 983-({[(1S)-6-methoxy-5-methyl-1,2,3,4-tetrahydronaphthalen-1- Byl]methyl}amino)pyridine-4-carboxylic acid 993-({[(1R)-6-methoxy-5-methyl-1,2,3,4-tetrahydronaphthalen-1- B Byl]methyl}amino)pyridine-4-carboxylic acid 1003-({[(4S)-7-(2-methylphenyl)-3,4-dihydro-2H-1-benzopyran-4- Cyl]methyl}amino)pyridine-4-carboxylic acid 1013-({[(4R)-7-(2-methylphenyl)-3,4-dihydro-2H-1-benzopyran-4- Byl]methyl}amino)pyridine-4-carboxylic acid 1023-({[(4R)-7-(5-fluoro-2-methoxyphenyl)-3,4-dihydro-2H-1- Bbenzopyran-4-yl]methyl}amino)pyridine-4-carboxylic acid 1033-({[(1R)-6-[(4-cyanophenyl)(methyl)amino]-1,2,3,4- Btetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 1043-({[(4R)-7-[(2,4-difluorophenyl)(methyl)amino]-3,4-dihydro-2H- B1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic acid 1053-({[(4R)-7-[methyl(3-methylphenyl)amino]-3,4-dihydro-2H-1- Bbenzopyran-4-yl]methyl}amino)pyridine-4-carboxylic acid 1063-({[(1R)-6-(pyrrolidin-1-yl)-1,2,3,4-tetrahydronaphthalen-1- Byl]methyl}amino)pyridine-4-carboxylic acid 1073-({[(4R)-7-(2-chloro-5-methoxyphenyl)-3,4-dihydro-2H-1- Bbenzopyran-4-yl]methyl}amino)pyridine-4-carboxylic acid 1083-({[(1R)-6-(3,4-dihydro-2H-1,4-benzoxazin-4-yl)-1,2,3,4- Ctetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 1093-({[(4R)-7-[(3,5-difluorophenyl)(methyl)amino]-3,4-dihydro-2H- B1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic acid 1103-({[(4R)-7-[(3-chlorophenyl)(methyl)amino]-3,4-dihydro-2H-1- Cbenzopyran-4-yl]methyl}amino)pyridine-4-carboxylic acid 1113-({[(4R)-7-[methyl(2-methylphenyl)amino]-3,4-dihydro-2H-1- Bbenzopyran-4-yl]methyl}amino)pyridine-4-carboxylic acid 1123-({[(4R)-7-[(4-fluoro-3-methoxyphenyl)(methyl)amino]-3,4- Bdihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4- carboxylic acid113 3-({[(1R)-6-[methyl(oxan-4-yl)amino]-1,2,3,4- Btetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 1143-({[(1R)-6-[(4-fluoro-3-methoxyphenyl)(methyl)amino]-1,2,3,4- Btetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 1153-({[(1R)-6-[(3-cyanophenyl)(methyl)amino]-1,2,3,4- Btetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 1163-({[(4R)-7-(2-methoxyphenyl)-3,4-dihydro-2H-1-benzopyran-4- Byl]methyl}amino)pyridine-4-carboxylic acid 1173-({[(4R)-7-[(3-cyanophenyl)(methyl)amino]-3,4-dihydro-2H-1- Bbenzopyran-4-yl]methyl}amino)pyridine-4-carboxylic acid 1183-({[(4R)-7-(4-fluoro-2-methoxyphenyl)-3,4-dihydro-2H-1- Bbenzopyran-4-yl]methyl}amino)pyridine-4-carboxylic acid 1193-({[(4R)-7-[(4-cyanophenyl)(methyl)amino]-3,4-dihydro-2H-1- Bbenzopyran-4-yl]methyl}amino)pyridine-4-carboxylic acid 1203-({[(1R)-6-[(cyclopropylmethyl)(methyl)amino]-1,2,3,4- Btetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 1213-({[(1R)-6-[methyl(6-methoxypyridin-2-yl)amino]-1,2,3,4- Btetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 1223-({[(1R)-6-[methyl(5-methylpyridin-2-yl)amino]-1,2,3,4- B Ctetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 1233-({[(1R)-6-[methyl(6-methylpyridin-2-yl)amino]-1,2,3,4- B Ctetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 1243-({[(4R)-7-(2-cyanophenyl)-3,4-dihydro-2H-1-benzopyran-4- Byl]methyl}amino)pyridine-4-carboxylic acid 1253-({[(1R)-6-[methyl(1-methyl-1H-pyrazol-3-yl)amino]-1,2,3,4- Btetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 1263-({[(4R)-7-[(4-ethynylphenyl)(methyl)amino]-3,4-dihydro-2H-1- B Cbenzopyran-4-yl]methyl}amino)pyridine-4-carboxylic acid 1273-({[(4R)-7-[(1,3-dihydro-2-benzofuran-5-yl)(methyl)amino]-3,4- Bdihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4- carboxylic acid128 3-({[(4R)-7-{methyl[4-(trifluoromethyl)phenyl]amino}-3,4- Cdihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4- carboxylic acid129 3-[({7-[phenyl(2,2,2-trifluoroethyl)amino]-3,4-dihydro-2H-1- Cbenzopyran-4-yl}methyl)amino]pyridine-4-carboxylic acid 1303-({[(1R)-6-[benzyl(methyl)amino]-1,2,3,4-tetrahydronaphthalen-1- B Cyl]methyl}amino)pyridine-4-carboxylic acid 1313-({[(4R)-7-[(2,3-dihydro-1H-inden-5-yl)(methyl)amino]-3,4- B Cdihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4- carboxylic acid132 3-({[(1R)-6-[(1,3-dihydro-2-benzofuran-5-yl)(methyl)amino]- B1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4- carboxylicacid 133 3-({[(1R)-6-[cyclopentyl(methyl)amino]-1,2,3,4- Btetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 1343-({[(4R)-7-[(4-cyclopropylphenyl)(methyl)amino]-3,4-dihydro- B C2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic acid 1353-({[(1R)-6-[(1-benzofuran-6-yl)(methyl)amino]-1,2,3,4- Btetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 1363-({[(4R)-7-[(1-benzofuran-5-yl)(methyl)amino]-3,4-dihydro-2H-1- Bbenzopyran-4-yl]methyl}amino)pyridine-4-carboxylic acid 1373-({[(1R)-6-[(1-benzofuran-5-yl)(methyl)amino]-1,2,3,4- Ctetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 1383-({[(4R)-7-(2-hydroxyphenyl)-3,4-dihydro-2H-1-benzopyran-4- B Cyl]methyl}amino)pyridine-4-carboxylic acid 1393-({[(4R)-7-[methyl(2-methyl-1,3-thiazol-4-yl)amino]-3,4-dihydro- B2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic acid 1403-({[(1R)-6-[methyl(4-methylphenyl)amino]-1,2,3,4- B Ctetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 1413-({[(4R)-7-[(1-benzofuran-6-yl)(methyl)amino]-3,4-dihydro-2H-1- Bbenzopyran-4-yl]methyl}amino)pyridine-4-carboxylic acid 1423-[(3,4-dihydro-1H-2-benzopyran-1-ylmethyl)amino]pyridine-4- Bcarboxylic acid 143 3-({[(1R)-6-[methyl(3-methylphenyl)amino]-1,2,3,4- Ctetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 1443-({[(1R)-6-[methyl(thiophen-2-yl)amino]-1,2,3,4- Btetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 1453-({[(4R)-7-[methyl(5-methylpyridin-2-yl)amino]-3,4-dihydro-2H- A C1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic acid 1463-[({6-[methyl(phenyl)amino]-3,4-dihydro-1H-2-benzopyran-1- Byl}methyl)amino]pyridine-4-carboxylic acid 1473-({[(1R)-6-[(2-hydroxyethyl)(phenyl)amino]-1,2,3,4- Btetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 1483-({[(4R)-7-[methyl(6-methylpyridin-2-yl)amino]-3,4-dihydro-2H- B1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic acid 1493-[(1,2,3,4-tetrahydroisoquinolin-1-ylmethyl)amino]pyridine-4- Bcarboxylic acid 1503-({[(1R)-6-[(3-methoxyphenyl)(methyl)amino]-1,2,3,4- Btetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 1513-({[(4R)-7-[(3-fluoro-4-methylphenyl)(methyl)amino]-3,4- Bdihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4- carboxylic acid152 3-({[(4R)-7-[(5-chloropyridin-2-yl)(methyl)amino]-3,4-dihydro- B2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic acid 1533-({[(4R)-7-[(5-cyclopropylpyridin-2-yl)(methyl)amino]-3,4- B Cdihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4- carboxylic acid154 3-({[(4R)-7-[(4-ethylphenyl)(methyl)amino]-3,4-dihydro-2H-1- B Cbenzopyran-4-yl]methyl}amino)pyridine-4-carboxylic acid 1553-({[(1R)-6-[methyl(1-methyl-2-oxo-1,2-dihydropyridin-4- Byl)amino]-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 1563-({[(1R)-6-[methyl(5-methylpyrimidin-2-yl)amino]-1,2,3,4- B Ctetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 1573-({[(4R)-7-[(5-ethylpyridin-2-yl)(methyl)amino]-3,4-dihydro-2H- B C1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic acid 1583-({[(1R)-6-{[4-(hydroxymethyl)phenyl](methyl)amino}-1,2,3,4- Btetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 1593-({[(1R)-6-[methyl(1-methyl-1H-pyrazol-4-yl)amino]-1,2,3,4- B Ctetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 1603-({[(1R)-6-{[4-(dimethylamino)phenyl](methyl)amino}-1,2,3,4- B Ctetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 1613-({[(1R)-6-[(4-cyclopropylphenyl)(methyl)amino]-1,2,3,4- Ctetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 1623-({[(1R)-6-(2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)-1,2,3,4- Ctetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 1633-({[(1R)-6-[(4-cyclopropylphenyl)(2-methoxyethyl)amino]- C1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4- carboxylicacid 164 3-({[(1R)-6-{[4-(methoxymethyl)phenyl](methyl)amino}-1,2,3,4- BC tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 1653-({[(1R)-6-[(4-hydroxyphenyl)(methyl)amino]-1,2,3,4- B Ctetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 1663-({[(1R)-6-[(dimethyl-1,2-oxazol-4-yl)(methyl)amino]-1,2,3,4- B Ctetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 1673-({[(1R)-6-{methyl[4-(pyrrolidin-1-yl)phenyl]amino}-1,2,3,4- Btetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 1683-({[(1R)-6-({4-[(1R)-1-hydroxyethyl]phenyl}(methyl)amino)- B1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4- carboxylicacid 169 3-({[(1R)-6-({4-[(1S)-1-hydroxyethyl]phenyl}(methyl)amino)- B1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4- carboxylicacid 170 3-({[(1R)-6-{methyl[4-(morpholin-4-yl)phenyl]amino}-1,2,3,4- BC tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 1713-({[(1R)-6-[methyl(5-methyl-1,2-oxazol-3-yl)amino]-1,2,3,4- Ctetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 1723-({[(1R)-6-[(2-methoxyphenyl)(methyl)amino]-1,2,3,4- Btetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 1733-({[(1R)-6-[methyl(pyridin-4-yl)amino]-1,2,3,4- Atetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 1743-({[(1R)-6-{[4-(3,6-dihydro-2H-pyran-4- Cyl)phenyl](methyl)amino}-1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 1753-({[(1R)-6-{methyl[4-(oxan-4-yl)phenyl]amino}-1,2,3,4- Ctetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 1763-({[(4R)-7-[(4-ethenylphenyl)(methyl)amino]-3,4-dihydro-2H-1- Bbenzopyran-4-yl]methyl}amino)pyridine-4-carboxylic acid 1773-({[(1R)-6-[(4-methoxyphenyl)(methyl)amino]-1,2,3,4- Btetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 1783-({[(4R)-7-[(4-methoxyphenyl)(methyl)amino]-3,4-dihydro-2H-1- Abenzopyran-4-yl]methyl}amino)pyridine-4-carboxylic acid 1793-({[(4R)-7-{methyl[4-(pyrrolidin-1-yl)phenyl]amino}-3,4- Bdihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4- carboxylic acid180 3-({[(1R)-6-{[4-(azetidin-1-yl)phenyl](methyl)amino}-1,2,3,4- Btetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 1813-({[(1R)-6-{methyl[4-(trifluoromethoxy)phenyl]amino}-1,2,3,4- Btetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 1823-({[(4R)-7-{methyl[4-(trifluoromethoxy)phenyl]amino}-3,4- B Cdihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4- carboxylic acid183 3-({[(4R)-7-{[4-(azetidin-1-yl)phenyl](methyl)amino}-3,4-dihydro- BC 2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic acid 1843-({[(1R)-6-{[4-(difluoromethoxy)phenyl](methyl)amino}-1,2,3,4- B Ctetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 1853-({[(1R)-6-[(4-ethoxyphenyl)(methyl)amino]-1,2,3,4- B Ctetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 1863-({[(4R)-7-[(4-ethoxyphenyl)(methyl)amino]-3,4-dihydro-2H-1- Bbenzopyran-4-yl]methyl}amino)pyridine-4-carboxylic acid 1873-({[(4R)-7-{methyl[4-(propan-2-yl)phenyl]amino}-3,4-dihydro- B C2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic acid 1883-({[(1R)-6-{methyl[4-(1H-pyrazol-1-yl)phenyl]amino}-1,2,3,4- Btetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 1893-({[(4R)-7-{methyl[4-(1H-pyrazol-1-yl)phenyl]amino}-3,4- Bdihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4- carboxylic acid190 3-({[(4R)-7-{[4-(difluoromethoxy)phenyl](methyl)amino}-3,4- B Cdihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4- carboxylic acid191 3-({[(1R)-6-[methyl(phenyl)amino]-1,2,3,4-tetrahydronaphthalen- B C1-yl]methyl}amino)pyridazine-4-carboxylic acid 1923-({[(4R)-7-{methyl[4-(2,2,2-trifluoroethyl)phenyl]amino}-3,4- B Cdihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4- carboxylic acid193 3-({[(1R)-6-{[4-(1H-imidazol-1-yl)phenyl](methyl)amino}-1,2,3,4- B Ctetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 1943-({[(4R)-7-{[4-(1H-imidazol-1-yl)phenyl](methyl)amino}-3,4- B Cdihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4- carboxylic acid195 3-({[(1R)-6-{[4-(3,3-difluoroazetidin-1-yl)phenyl](methyl)amino}- B1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4- carboxylicacid 1963-({[(4R)-7-{[4-(3,3-difluoroazetidin-1-yl)phenyl](methyl)amino}- B3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4- carboxylicacid 197 3-({[(1R)-6-{[4-(2-methoxyethoxy)phenyl](methyl)amino}-1,2,3,4-B tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4-carboxylic acid 1983-({[(4R)-7-(1-phenylethyl)-3,4-dihydro-2H-1-benzopyran-4- Byl]methyl}amino)pyridine-4-carboxylic acid 1993-({[(4R)-7-{methyl[5-(propan-2-yl)pyridin-2-yl]amino}-3,4- Bdihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4- carboxylic acid200 3-({[(1R)-6-{[4-(3-hydroxyazetidin-1-yl)phenyl](methyl)amino}- B1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4- carboxylicacid 201 3-({[(4R)-7-{[4-(3,6-dihydro-2H-pyran-4- Byl)phenyl](methyl)amino}-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic acid 2023-({[(4R)-7-{methyl[4-(oxan-4-yl)phenyl]amino}-3,4-dihydro-2H- B C1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic acid 2033-({[(4R)-7-(1-phenylcyclopropyl)-3,4-dihydro-2H-1-benzopyran- B4-yl]methyl}amino)pyridine-4-carboxylic acid 2043-({[(4R)-7-{methyl[4-(1-methyl-1,2,3,6-tetrahydropyridin-4- Ayl)phenyl]amino}-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic acid 2053-({[(4R)-7-{methyl[4-(1-methylpiperidin-4-yl)phenyl]amino}-3,4- Adihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4- carboxylic acid206 3-({[(4R)-7-[(3,4-dimethylphenyl)(methyl)amino]-3,4-dihydro-2H- B1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic acid 2073-({[(4R)-7-{[4-(2-hydroxyethyl)phenyl](methyl)amino}-3,4- Bdihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4- carboxylic acid208 3-({[(4R)-7-[methyl(4-propylphenyl)amino]-3,4-dihydro-2H-1- Cbenzopyran-4-yl]methyl}amino)pyridine-4-carboxylic acid 2093-({[(1R)-6-{[4-(cyclopropylmethoxy)phenyl](methyl)amino}- B C1,2,3,4-tetrahydronaphthalen-1-yl]methyl}amino)pyridine-4- carboxylicacid 210 3-({[(4R)-7-{methyl[4-(propan-2-yloxy)phenyl]amino}-3,4- Bdihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4- carboxylic acid211 3-({[(4R)-7-{[4-(cyclopropylmethoxy)phenyl](methyl)amino}-3,4- Bdihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4- carboxylic acid212 3-({[(4R)-7-[methyl(4-propoxyphenyl)amino]-3,4-dihydro-2H-1- Bbenzopyran-4-yl]methyl}amino)pyridine-4-carboxylic acid 2133-({[(4R)-7-[(4-cyclopropoxyphenyl)(methyl)amino]-3,4-dihydro- B2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylic acid 2143-({[(4R)-7-{methyl[4-(2,2,2-trifluoroethoxy)phenyl]amino}-3,4- Bdihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4- carboxylic acid215 3-({[(4R)-7-{[4-(cyclopropylmethyl)phenyl](methyl)amino}-3,4- Bdihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4- carboxylic acid216 3-({[(4R)-7-[(4-cyclopropanecarbonylphenyl)(methyl)amino]-3,4- Bdihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4- carboxylic acidNote: Biochemical assay IC₅₀ data are designated within the followingranges: A: ≤100 nM B: >100 nM to ≤1000 nM C: >1000 nM to ≤10,000 nMD: >10,000 nM

The ability of the following two compounds to inhibit JMJD3 or JMJD2Cunder the enzymatic assay conditions described herein was determined.3-({[(4S)-7-phenyl-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylicacid (Example 83 of U.S. Pat. No. 8,952,151) had a JMJD3 IC₅₀ of 0.019μM and a JMJD2C IC₅₀ of 0.950 μM.3-({[(4R)-7-phenyl-3,4-dihydro-2H-1-benzopyran-4-yl]methyl}amino)pyridine-4-carboxylicacid (Example 84 of U.S. Pat. No. 8,952,151) had a JMJD3 IC₅₀ of 2.15 μMand a JMJD2C IC₅₀ of 0.150 μM. The S-enantiomer was >100-fold morepotent for JMJD3 than the R-enantiomer. The R-enantiomer was about6-fold more potent for JMJD2C than the S-enantiomer.

Example 2: In Vitro Cell-Based Assay

The primary cellular assay for JMJD2C inhibition is an assay whichmeasures cellular proliferation via Bromodeoxyuridine (BrdU)incorporation after 168 hours of compound incubation. Cell lines testedinclude the JMJD2C gene amplified cell line KYSE-150. This is aquantitative ELISA assay measuring DNA incorporation of BrdU duringS-phase as a direct readout of cellular proliferation.

Assay Principle: This is a colorimetric immunoassay for thequantification of cell proliferation. Cells treated for 168 hours withtest compounds are assayed for their ability to go through S-phase as ameasure of their proliferative potential.

Assay Method: The human KYSE-150 (SMAD4 mut, TP53 mut) esophagealcarcinoma cell line was seeded at 2,000 cells/well on a 96-well tissueculture treated plate. After an overnight incubation, cells were treatedwith compound in an 11-point dilution series with final concentrationsranging from 100 μM to 2 nM. Cells were then incubated in the presenceof compound for 168 hours. After compound incubation the cells wereassayed using a BrdU Cell Proliferation ELISA (Roche). The cells werefirst incubated with BrdU labeling reagent for 2 hours. After 2 hours,the BrdU incorporated cells were fixed and denatured, probed with ananti-BrdU-Peroxidase antibody for 1.5 hours and washed. Finally, atetramethylbenzidine peroxidase substrate was added to each well for 15minutes followed by a H₂SO₄ stop solution. The plate was read at 450 nm,and the raw optical density data was transferred into XLFit (IDBS) forIC₅₀ calculation using the formula:fit=(D+((Vmax*(x^n))/((x^n)+(Km^n))))

Table 4 provides the cellular IC₅₀ values of various compounds disclosedherein.

TABLE 4 Example Cellular IC₅₀ (μM) 2 A 3 D 4 B 5 B 6 A 7 A 8 A 9 A 10 A11 A 12 B 13 B 14 D 15 C 16 B 17 B 18 A 19 A 20 A 21 A 22 A 23 A 24 A 25D 26 C 27 C 28 C 30 B 32 C 34 B 35 C 37 B 38 D 40 A 42 B 43 A 44 B 45 B46 A 48 C 49 C 51 C 53 B 55 B 56 C 58 A 59 C 61 C 63 D 64 A 65 B 66 A 67B 69 B 71 B 73 B 73 B 77 A 79 A 80 C 82 D 84 D 86 D 88 D 89 D 91 C 92 C93 C 94 B 95 D 97 C 99 C 101 A 102 B 103 B 104 B 105 A 106 B 109 B 110 A111 B 112 C 114 B 115 B 116 B 117 B 119 B 120 B 121 A 122 A 123 A 124 C125 B 126 B 127 B 131 A 132 A 133 C 134 A 135 A 136 A 139 A 140 A 141 B142 D 144 A 145 A 146 A 147 B 148 B 150 A 151 A 152 B 153 A 154 A 155 D156 B 157 A 158 B 159 C 160 A 161 A 163 A 164 A 165 C 166 D 167 A 168 A169 A 170 A 171 D 172 B 173 D 174 A 175 A 176 A 177 A 178 A 179 A 180 A183 A 184 A 185 A 186 A 187 A 188 A 189 B 190 A 191 A 192 A 193 B 194 C196 A 197 A 198 A 199 A 200 B 201 A 202 A 203 B 204 D 205 D 206 A 207 B208 A 209 A 210 A 211 A 212 A 213 A 214 A Note: Biochemical assay IC₅₀data are designated within the following ranges: A: ≤0.10 μM B: >0.10 μMto ≤1.0 μM C: >1.0 μM to ≤10 μM D: >10 μM

Example 3: In Vivo Xenograph Study

Time release pellets containing 0.72 mg 17-β Estradiol aresubcutaneously implanted into nu/nu mice. MCF-7 cells are grown in RPMIcontaining 10% FBS at 5% CO₂, 37° C. Cells are spun down andre-suspended in 50% RPMI (serum free) and 50% Matrigel at 1×10⁷cells/mL. MCF-7 cells are subcutaneously injected (100 μL/animal) on theright flank 2-3 days post pellet implantation and tumor volume(length×width²/2) is monitored bi-weekly. When tumors reach an averagevolume of ˜200 mm³ animals are randomized and treatment is started.Animals are treated with vehicle or compound daily for 4 weeks. Tumorvolume and body weight are monitored bi-weekly throughout the study. Atthe conclusion of the treatment period, plasma and tumor samples aretaken for pharmacokinetic and pharmacodynamic analyses, respectively.

III. Preparation of Pharmaceutical Dosage Forms Example 1: Oral Tablet

A tablet is prepared by mixing 48% by weigh of a compound of Formula (I)or a pharmaceutically acceptable salt thereof, 45% by weight ofmicrocrystalline cellulose, 5% by weight of low-substitutedhydroxypropyl cellulose, and 2% by weight of magnesium stearate. Tabletsare prepared by direct compression. The total weight of the compressedtablets is maintained at 250-500 mg.

We claim:
 1. A method of treating esophageal cancer in a subject in needthereof, comprising administering to the subject an effective amount ofa composition comprising Formula (II), or pharmaceutically acceptablesalt thereof:

wherein, X is O; R⁶ is chosen from optionally substituted heterocyclyl,optionally substituted heterocyclyloxy, optionally substitutedheterocyclylalkyl, optionally substituted heterocyclylalkoxy, optionallysubstituted C₆-C₁₀ aryl-SO₂-, optionally substituted heteroaryl-S—, orN(R¹)(R²), wherein R¹ is hydrogen or optionally substituted alkyl, andR² is chosen from optionally substituted alkyl, optionally substitutedaryl, optionally substituted heteroaryl, optionally substitutedheterocyclyl, optionally substituted cycloalkyl, optionally substitutedcycloalkylalkyl, optionally substituted aryl-CO—, optionally substitutedheteroaryl-CO—, optionally substituted cycloalkyl-CO—, or optionallysubstituted alkyl-CO—; and each R⁵, R⁷ and R⁸ is independently chosenfrom hydrogen, halogen, —OH, —CN, optionally substituted C₁-C₆ alkyl,optionally substituted C₁-C₆ alkoxy, optionally substituted C₃-C₇carbocyclyl, optionally substituted C₃-C₇ carbocyclyloxy, optionallysubstituted C₄-C₁₂ carbocyclylalkyl, optionally substituted C₄-C₁₂carbocyclylalkoxy, optionally substituted C₂-C₆ alkynyl, optionallysubstituted C₂-C₆ alkenyl, optionally substituted C₆-C₁₀ aryl,optionally substituted C₆-C₁₀ aryloxy, optionally substituted C₆-C₁₀aryl-S—, optionally substituted C₇-C₁₄ aralkoxy, optionally substitutedheteroaryl, and optionally substituted heteroaryloxy, optionallysubstituted heterocyclyl, optionally substituted heterocyclyloxy,substituted heterocyclylalkyl, optionally substitutedheterocyclylalkoxy, optionally substituted C₆-C₁₀ aryl-SO₂—, optionallysubstituted heteroaryl-S—, or —N(R¹)(R²), wherein R¹ is hydrogen oroptionally substituted alkyl, and R² is chosen from optionallysubstituted alkyl, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted heterocyclyl, optionally substitutedcycloalkyl, optionally substituted cycloalkylalkyl, optionallysubstituted aryl-CO—, optionally substituted heteroaryl-CO—, optionallysubstituted cycloalkyl-CO—, or optionally substituted alkyl-CO—; withthe provision that at least one of R⁵, R⁷ and R⁸ is hydrogen.
 2. Amethod of treating esophageal cancer in a subject in need thereof,comprising administering to the subject an effective amount of acomposition comprising Formula (IIa), or pharmaceutically acceptablesalt thereof:

wherein, X is O; R⁶ is chosen from optionally substituted heterocyclyl,optionally substituted heterocyclyloxy, optionally substitutedheterocyclylalkyl, optionally substituted heterocyclylalkoxy, optionallysubstituted C₆-C₁₀ aryl-SO₂—, optionally substituted heteroaryl-S—, orN(R¹)(R²), wherein R¹ is hydrogen or optionally substituted alkyl, andR² is chosen from optionally substituted alkyl, optionally substitutedaryl, optionally substituted heteroaryl, optionally substitutedheterocyclyl, optionally substituted cycloalkyl, optionally substitutedcycloalkylalkyl, optionally substituted aryl-CO—, optionally substitutedheteroaryl-CO—, optionally substituted cycloalkyl-CO—, or optionallysubstituted alkyl-CO—; and each R⁵, R⁷ and R⁸ is independently chosenfrom hydrogen, halogen, —OH, —CN, optionally substituted C₁-C₆ alkyl,optionally substituted C₁-C₆ alkoxy, optionally substituted C₃-C₇carbocyclyl, optionally substituted C₃-C₇ carbocyclyloxy, optionallysubstituted C₄-C₁₂ carbocyclylalkyl, optionally substituted C₄-C₁₂carbocyclylalkoxy, optionally substituted C₂-C₆ alkynyl, optionallysubstituted C₂-C₆ alkenyl, optionally substituted C₆-C₁₀ aryl,optionally substituted C₆-C₁₀ aryloxy, optionally substituted C₆-C₁₀aryl-S-, optionally substituted C₇-C₁₄ aralkoxy, optionally substitutedheteroaryl, and optionally substituted heteroaryloxy, optionallysubstituted heterocyclyl, optionally substituted heterocyclyloxy,substituted heterocyclylalkyl, optionally substitutedheterocyclylalkoxy, optionally substituted C₆-C₁₀ aryl-SO₂-, optionallysubstituted heteroaryl-S-, or —N(R¹)(R²), wherein R¹ is hydrogen oroptionally substituted alkyl, and R² is chosen from optionallysubstituted alkyl, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted heterocyclyl, optionally substitutedcycloalkyl, optionally substituted cycloalkylalkyl, optionallysubstituted aryl-CO—, optionally substituted heteroaryl-CO—, optionallysubstituted cycloalkyl-CO—, or optionally substituted alkyl-CO-; withthe provision that at least one of R⁵, R⁷ and R⁸ is hydrogen.
 3. Themethod of claim 2, wherein R⁵ is hydrogen.
 4. The method of claim 2,wherein R⁷ is hydrogen.
 5. The method of claim 2, wherein R⁸ ishydrogen.
 6. The method of claim 2, wherein R⁵, R⁷ and R⁸ are hydrogen.7. The method of claim 2, wherein R⁶ is optionally substitutedheterocyclyl, or optionally substituted heterocyclyloxy.
 8. The methodof claim 2, wherein R⁶ is optionally substituted C₆-C₁₀ aryl-SO₂—, oroptionally substituted heteroaryl-S—.
 9. The method of claim 2, whereinR⁶ is —N(R¹)(R²), wherein R¹ is hydrogen; and R² is chosen fromoptionally substituted alkyl, optionally substituted aryl, optionallysubstituted heteroaryl, optionally substituted heterocyclyl, optionallysubstituted cycloalkyl, optionally substituted cycloalkylalkyl,optionally substituted aryl-CO—, optionally substituted heteroaryl-CO—,optionally substituted cycloalkyl-CO—, or optionally substitutedalkyl-CO—.
 10. The method of claim 2, wherein R⁶ is —N(R¹)(R²), whereinR¹ is optionally substituted alkyl; and R² is chosen from optionallysubstituted alkyl, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted heterocyclyl, optionally substitutedcycloalkyl, optionally substituted cycloalkylalkyl, optionallysubstituted aryl-CO—, optionally substituted heteroaryl-CO—, optionallysubstituted cycloalkyl-CO—, or optionally substituted alkyl-CO—.
 11. Themethod of claim 6, wherein R⁶ is —N(R¹)(R²), wherein R¹ is optionallysubstituted alkyl; and R² is chosen from optionally substituted alkyl,optionally substituted aryl, optionally substituted heteroaryl,optionally substituted heterocyclyl, optionally substituted cycloalkyl,optionally substituted cycloalkylalkyl, optionally substituted aryl-CO—,optionally substituted heteroaryl-CO—, optionally substitutedcycloalkyl-CO—, or optionally substituted alkyl-CO—.
 12. The method ofclaim 11, wherein R² is optionally substituted aryl.
 13. The method ofclaim 11, wherein R² is optionally substituted heteroaryl.
 14. Themethod of claim 11, wherein R² is optionally substituted heterocyclyl,optionally substituted cycloalkyl, optionally substitutedcycloalkylalkyl, optionally substituted aryl-CO—, optionally substitutedcycloalkyl-CO—, or optionally substituted alkyl-CO—.
 15. The method ofclaim 12, wherein R¹ is an optionally substituted C1-C3 alkyl.
 16. Themethod of claim 12, wherein R¹ is CH₃ group.
 17. The method of claim 12,wherein the optionally substituted aryl is substituted with at least onesubstituent selected from optionally substituted C1-C5 alkyl, optionallysubstituted C2-C5 alkenyl, halogen, cyano, hydroxy, amino, optionallysubstituted C1-C5 alkoxy, optionally substituted alkylamino, optionallysubstituted dialkylamino, optionally substituted heterocyclyl,optionally substituted heteroaryl, optionally substituted cycloalkyl,optionally substituted cycloalkylalkyl, optionally substitutedcycloalkylalkoxy, or optionally substituted cycloalkoxy.
 18. The methodof claim 12, wherein the optionally substituted aryl is substituted withat least one substituent selected from optionally substituted C1-C5alkyl, halogen, optionally substituted C1-C5 alkoxy, optionallysubstituted heterocyclyl, optionally substituted heteroaryl, optionallysubstituted cycloalkyl, optionally substituted cycloalkylalkyl,optionally substituted cycloalkylalkoxy, or optionally substitutedcycloalkoxy.
 19. The method of claim 12, wherein the optionallysubstituted aryl is substituted with at least one substituent selectedfrom optionally substituted heterocyclyl, optionally substitutedheteroaryl, optionally substituted cycloalkyl, optionally substitutedcycloalkylalkyl, optionally substituted cycloalkylalkoxy, or optionallysubstituted cycloalkoxy.
 20. The method of claim 12, wherein theoptionally substituted aryl is substituted with at least one substituentselected from optionally substituted C1-C5 alkyl, halogen, or optionallysubstituted C1-C5 alkoxy.
 21. The method of claim 12, wherein theoptionally substituted aryl is substituted with at least one optionallysubstituted C1-C5 alkyl.
 22. The method of claim 20, wherein R¹ is a CH₃group, and X is O.
 23. The method of claim 2, wherein the compound hasthe structure:


24. The method of claim 2, wherein the compound has the structure:


25. The method of claim 2, wherein the compound has the structure:


26. The method of claim 2, wherein the compound has the structure:


27. The method of claim 2, wherein the compound has the structure: